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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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13 pages, 4673 KB  
Article
Endocytic Pathway of Feline Coronavirus for Cell Entry: Differences in Serotype-Dependent Viral Entry Pathway
by Tomomi Takano, Yumeho Wakayama and Tomoyoshi Doki
Pathogens 2019, 8(4), 300; https://doi.org/10.3390/pathogens8040300 - 16 Dec 2019
Cited by 17 | Viewed by 8846
Abstract
Feline coronavirus (FCoV) is a pathogen causing a lethal infectious disease in cats, feline infectious peritonitis. It has two serotypes (type I FCoV and type II FCoV). According to our previous study, type I FCoV infection is inhibited by compounds inducing intracellular cholesterol [...] Read more.
Feline coronavirus (FCoV) is a pathogen causing a lethal infectious disease in cats, feline infectious peritonitis. It has two serotypes (type I FCoV and type II FCoV). According to our previous study, type I FCoV infection is inhibited by compounds inducing intracellular cholesterol accumulation, whereas type II FCoV infection is not inhibited. Intracellular cholesterol accumulation was reported to disrupt late endosome function. Based on these findings, types I and II FCoV are considered to enter the cytosol through late and early endosomes, respectively. We investigated whether the antiviral activities of a late endosome trafficking inhibitor and cholesterol-accumulating agents are different between the FCoV serotypes. The late endosome trafficking inhibitor did not inhibit type II FCoV infection, but it inhibited type I FCoV infection. Type I FCoV infection was inhibited by cholesterol-accumulating triazoles, but not by non-cholesterol-accumulating triazoles. These phenomena were observed in both feline cell lines and feline primary macrophages. This study provides additional information on the differences in intracellular reproductive cycle between type I and type II FCoV. Full article
(This article belongs to the Special Issue Feline Infectious Peritonitis)
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13 pages, 1596 KB  
Article
Genetic Basis and Physiological Effects of Lipid A Hydroxylation in Pseudomonas aeruginosa PAO1
by Alessandra Lo Sciuto, Matteo Cervoni, Roberta Stefanelli, Maria Concetta Spinnato, Alessandra Di Giamberardino, Carmine Mancone and Francesco Imperi
Pathogens 2019, 8(4), 291; https://doi.org/10.3390/pathogens8040291 - 10 Dec 2019
Cited by 22 | Viewed by 4449
Abstract
Modifications of the lipid A moiety of lipopolysaccharide influence the physicochemical properties of the outer membrane of Gram-negative bacteria. Some bacteria produce lipid A with a single hydroxylated secondary acyl chain. This hydroxylation is catalyzed by the dioxygenase LpxO, and is important for [...] Read more.
Modifications of the lipid A moiety of lipopolysaccharide influence the physicochemical properties of the outer membrane of Gram-negative bacteria. Some bacteria produce lipid A with a single hydroxylated secondary acyl chain. This hydroxylation is catalyzed by the dioxygenase LpxO, and is important for resistance to cationic antimicrobial peptides (e.g., polymyxins), survival in human blood, and pathogenicity in animal models. The lipid A of the human pathogen Pseudomonas aeruginosa can be hydroxylated in both secondary acyl chains, but the genetic basis and physiological role of these hydroxylations are still unknown. Through the generation of single and double deletion mutants in the lpxO1 and lpxO2 homologs of P. aeruginosa PAO1 and lipid A analysis by mass spectrometry, we demonstrate that both LpxO1 and LpxO2 are responsible for lipid A hydroxylation, likely acting on different secondary acyl chains. Lipid A hydroxylation does not appear to affect in vitro growth, cell wall stability, and resistance to human blood or antibiotics in P. aeruginosa. In contrast, it is required for infectivity in the Galleria mellonella infection model, without relevantly affecting in vivo persistence. Overall, these findings suggest a role for lipid A hydroxylation in P. aeruginosa virulence that could not be directly related to outer membrane integrity. Full article
(This article belongs to the Section Human Pathogens)
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18 pages, 3669 KB  
Article
Phenotypic Characterization of Rhodococcus equi Biofilm Grown In Vitro and Inhibiting and Dissolving Activity of Azithromycin/Rifampicin Treatment
by Elisa Rampacci, Maria Luisa Marenzoni, Stefano Giovagnoli, Fabrizio Passamonti, Mauro Coletti and Donatella Pietrella
Pathogens 2019, 8(4), 284; https://doi.org/10.3390/pathogens8040284 - 4 Dec 2019
Cited by 8 | Viewed by 4241
Abstract
Microbial biofilm has been implicated in a wide range of chronic infections. In spite of the fact that Rhodococcus equi is a recognized cause of chronic disease in animals and humans, few studies have focused on the sessile phenotype of R. equi. [...] Read more.
Microbial biofilm has been implicated in a wide range of chronic infections. In spite of the fact that Rhodococcus equi is a recognized cause of chronic disease in animals and humans, few studies have focused on the sessile phenotype of R. equi. The aim of this research was to phenotypically characterize the biofilm development of R. equi and its answerability for hypo-responsiveness to macrolides and rifampicin. Biofilm formation is initiated by bacterial adhesion to the surface. In this work, the ability of R. equi to adhere to the surface of human lung epithelial cells was detected by a fluorometric adhesion test performed on 40 clinical isolates. Subsequently, the capability of R. equi to produce biofilm was investigated by colorimetric, fluorescence and scanning electron microscopy analysis, revealing a general slow growth of rhodococcal biofilm and different sessile phenotypes among field isolates, some also including filamented bacteria. Azithromycin treatment produced a higher long-term inhibition and dissolution of R. equi biofilms than rifampicin, while the two antibiotics combined boosted the anti-biofilm effect in a statistically significant manner, although this was not equally effective for all R. equi isolates. Increasing the MIC concentrations of drugs tenfold alone and in combination did not completely eradicate pre-formed R. equi biofilms, while a rifampicin-resistant isolate produced an exceptionally abundant extracellular matrix. These results have strengthened the hypothesis that biofilm production may occur as an antibiotic tolerance system in R. equi, potentially determining persistence and, eventually, chronic infection. Full article
(This article belongs to the Section Animal Pathogens)
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13 pages, 1679 KB  
Article
Transcriptomic Analysis of Aggregatibacter actinomycetemcomitans Core and Accessory Genes in Different Growth Conditions
by Natalia O. Tjokro, Weerayuth Kittichotirat, Annamari Torittu, Riikka Ihalin, Roger E. Bumgarner and Casey Chen
Pathogens 2019, 8(4), 282; https://doi.org/10.3390/pathogens8040282 - 3 Dec 2019
Cited by 5 | Viewed by 3547
Abstract
Aggregatibacter actinomycetemcomitans genome can be divided into an accessory gene pool (found in some but not all strains) and a core gene pool (found in all strains). The functions of the accessory genes (genomic islands and non-island accessory genes) are largely unknown. We [...] Read more.
Aggregatibacter actinomycetemcomitans genome can be divided into an accessory gene pool (found in some but not all strains) and a core gene pool (found in all strains). The functions of the accessory genes (genomic islands and non-island accessory genes) are largely unknown. We hypothesize that accessory genes confer critical functions for A. actinomycetemcomitans in vivo. This study examined the expression patterns of accessory and core genes of A. actinomycetemcomitans in distinct growth conditions. We found similar expression patterns of island and non-island accessory genes, which were generally lower than the core genes in all growth conditions. The median expression levels of genomic islands were 29%–37% of the core genes in enriched medium but elevated to as high as 63% of the core genes in nutrient-limited media. Several putative virulence genes, including the cytolethal distending toxin operon, were found to be activated in nutrient-limited conditions. In conclusion, genomic islands and non-island accessory genes exhibited distinct patterns of expression from the core genes and may play a role in the survival of A. actinomycetemcomitans in nutrient-limited environments. Full article
(This article belongs to the Special Issue Aggregatibacter actinomycetemcomitans—Gram-Negative Bacterial Pathogen)
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9 pages, 267 KB  
Article
The Prevalence of HSV, HHV-6, HPV and Mycoplasma genitalium in Chlamydia trachomatis positive and Chlamydia trachomatis Negative Urogenital Samples among Young Women in Finland
by Suvi Korhonen, Kati Hokynar, Tiina Eriksson, Kari Natunen, Jorma Paavonen, Matti Lehtinen and Mirja Puolakkainen
Pathogens 2019, 8(4), 276; https://doi.org/10.3390/pathogens8040276 - 1 Dec 2019
Cited by 8 | Viewed by 4698
Abstract
Chlamydia trachomatis, Mycoplasma genitalium, herpes simplex virus (HSV) and human papillomavirus (HPV) cause sexually transmitted infections. In addition, human herpesvirus 6 (HHV-6) may be a genital co-pathogen. The prevalence rates of HSV, HHV-6, HPV, M. genitalium, and the C. trachomatis [...] Read more.
Chlamydia trachomatis, Mycoplasma genitalium, herpes simplex virus (HSV) and human papillomavirus (HPV) cause sexually transmitted infections. In addition, human herpesvirus 6 (HHV-6) may be a genital co-pathogen. The prevalence rates of HSV, HHV-6, HPV, M. genitalium, and the C. trachomatis ompA genotypes were investigated by PCR in urogenital samples of the C. trachomatis nucleic acid amplification test positive (n = 157) and age-, community- and time-matched negative (n = 157) women. The prevalence of HPV DNA was significantly higher among the C. trachomatis positives than the C. trachomatis negatives (66% vs. 25%, p < 0.001). The prevalence of HSV (1.9% vs. 0%), HHV-6 (11% vs. 14%), and M. genitalium DNA (4.5% vs. 1.9%) was not significantly different between the C. trachomatis-positive and -negative women. Thirteen per cent of test-of-cure specimens tested positive for C. trachomatis. The prevalence of HSV, HHV-6, HPV, M. genitalium, and the C. trachomatis ompA genotypes did not significantly differ between those who cleared the C. trachomatis infection (n = 105) and those who did not (n = 16). The higher prevalence of HPV DNA among the C. trachomatis positives suggests greater sexual activity and increased risk for sexually transmitted pathogens. Full article
(This article belongs to the Special Issue Chlamydia trachomatis Infections)
12 pages, 6108 KB  
Article
Immunosuppressive Compounds Affect the Fungal Growth and Viability of Defined Aspergillus Species
by Stanislaw Schmidt, Michael Hogardt, Asuman Demir, Frauke Röger and Thomas Lehrnbecher
Pathogens 2019, 8(4), 273; https://doi.org/10.3390/pathogens8040273 - 29 Nov 2019
Cited by 10 | Viewed by 3687
Abstract
Immunosuppressive drugs are administered to a number of patients; e.g., to allogeneic hematopoietic stem cell transplant recipients. Immunosuppressive drugs impair the immune system and thus increase the risk of invasive fungal disease, but may exhibit antifungal activity at the same time. We investigated [...] Read more.
Immunosuppressive drugs are administered to a number of patients; e.g., to allogeneic hematopoietic stem cell transplant recipients. Immunosuppressive drugs impair the immune system and thus increase the risk of invasive fungal disease, but may exhibit antifungal activity at the same time. We investigated the impact of various concentrations of three commonly used immunosuppressive compounds—cyclosporin A (CsA), methylprednisolone (mPRED), and mycophenolic acid (MPA)—on the growth and viability of five clinically important Aspergillus species. Methods included disc diffusion, optical density of mycelium, and viability assays such as XTT. MPA and CsA had a species-specific and dose-dependent inhibitory effect on the growth of all Aspergillus spp. tested, although growth inhibition by MPA was highest in A. niger, A. flavus and A. brasiliensis. Both agents exhibited species-specific hyphal damage, which was higher when the immunosuppressants were added to growing conidia than to mycelium. In contrast, mPRED increased the growth of A. niger, but had no major impact on the growth and viability of any of the other Aspergillus species tested. Our findings may help to better understand the interaction of drugs with Aspergillus species and ultimately may have an impact on individualizing immunosuppressive therapy. Full article
(This article belongs to the Section Human Pathogens)
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12 pages, 1066 KB  
Article
Genetic Diversity among Pseudorabies Viruses Isolated from Dogs in France from 2006 to 2018
by Céline Deblanc, Aurélie Oger, Gaëlle Simon and Marie-Frédérique Le Potier
Pathogens 2019, 8(4), 266; https://doi.org/10.3390/pathogens8040266 - 26 Nov 2019
Cited by 19 | Viewed by 3590
Abstract
Pseudorabies (PR), also known as Aujeszky’s disease, is an economically important disease for the pig industry. It has been eradicated in domestic pigs in many European countries, including France, but its causative agent—Suid Herpesvirus 1—is still circulating in wild boars. The risk of [...] Read more.
Pseudorabies (PR), also known as Aujeszky’s disease, is an economically important disease for the pig industry. It has been eradicated in domestic pigs in many European countries, including France, but its causative agent—Suid Herpesvirus 1—is still circulating in wild boars. The risk of endemic PR in wild fauna lies in reintroducing the virus among domestic pigs and transmitting it to other mammals, especially hunting dogs for which the disease is rapidly fatal. As such infections are regularly reported in France, this study genetically characterized canine PR virus strains in the country to obtain information on their diversity and evolution. Partial sequencing of the glycoprotein C-encoding gene from 55 virus strains isolated from dogs between 2006 and 2018 showed that 14 strains belonged to genotype I-clade A and another 38 to genotype I-clade B, two clades usually reported in Western Europe. More surprisingly, three strains were found to belong to genotype II, suggesting an Asian origin. Genotype I-clade A strains exhibited the highest diversity as five geographically segregated genogroups were identified. Full article
(This article belongs to the Special Issue Pseudorabies Virus Infections)
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21 pages, 8574 KB  
Article
Entry of Scotophilus Bat Coronavirus-512 and Severe Acute Respiratory Syndrome Coronavirus in Human and Multiple Animal Cells
by Yi-Ning Chen, Hsiao-Chin Hsu, Sheng-Wei Wang, Hao-Chiang Lien, Hsin-Ti Lu and Sheng-Kai Peng
Pathogens 2019, 8(4), 259; https://doi.org/10.3390/pathogens8040259 - 22 Nov 2019
Cited by 8 | Viewed by 8234
Abstract
Bats are natural reservoirs of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV). Scotophilus bat CoV-512 demonstrates potential for cross-species transmission because its viral RNA and specific antibodies have been detected in three bat species of Taiwan. Understanding [...] Read more.
Bats are natural reservoirs of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV). Scotophilus bat CoV-512 demonstrates potential for cross-species transmission because its viral RNA and specific antibodies have been detected in three bat species of Taiwan. Understanding the cell tropism of Scotophilus bat CoV-512 is the first step for studying the mechanism of cross-species transmission. In this study, a lentivirus-based pseudovirus was produced using the spike (S) protein of Scotophilus bat CoV-512 or SARS-CoV as a surface protein to test the interaction between coronaviral S protein and its cell receptor on 11 different cells. Susceptible cells expressed red fluorescence protein (RFP) after the entry of RFP-bound green fluorescence protein (GFP)-fused S protein of Scotophilus bat CoV-512 (RFP-Sco-S-eGFP) or RFP-SARS-S pseudovirus, and firefly luciferase (FLuc) activity expressed by cells infected with FLuc-Sco-S-eGFP or FLuc-SARS-S pseudovirus was quantified. Scotophilus bat CoV-512 pseudovirus had significantly higher entry efficiencies in Madin Darby dog kidney epithelial cells (MDCK), black flying fox brain cells (Pabr), and rat small intestine epithelial cells (IEC-6). SARS-CoV pseudovirus had significantly higher entry efficiencies in human embryonic kidney epithelial cells (HEK-293T), pig kidney epithelial cells (PK15), and MDCK cells. These findings demonstrated that Scotophilus bat CoV-512 had a broad host range for cross-species transmission like SARS-CoV. Full article
(This article belongs to the Section Animal Pathogens)
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41 pages, 6933 KB  
Article
Genome-Wide Analyses Revealed Remarkable Heterogeneity in Pathogenicity Determinants, Antimicrobial Compounds, and CRISPR-Cas Systems of Complex Phytopathogenic Genus Pectobacterium
by Dario Arizala and Mohammad Arif
Pathogens 2019, 8(4), 247; https://doi.org/10.3390/pathogens8040247 - 20 Nov 2019
Cited by 26 | Viewed by 7054
Abstract
The Pectobacterium genus comprises pectolytic enterobacteria defined as the causal agents of soft rot, blackleg, and aerial stem rot diseases of potato and economically important crops. In this study, we undertook extensive genome-wide comparative analyses of twelve species that conform the Pectobacterium genus. [...] Read more.
The Pectobacterium genus comprises pectolytic enterobacteria defined as the causal agents of soft rot, blackleg, and aerial stem rot diseases of potato and economically important crops. In this study, we undertook extensive genome-wide comparative analyses of twelve species that conform the Pectobacterium genus. Bioinformatics approaches outlined a low nucleotide identity of P. parmentieri and P. wasabiae with other species, while P. carotovorum subsp. odoriferum was shown to harbor numerous pseudogenes, which suggests low coding capacity and genomic degradation. The genome atlases allowed for distinguishing distinct DNA structures and highlighted suspicious high transcription zones. The analyses unveiled a noteworthy heterogeneity in the pathogenicity determinants. Specifically, phytotoxins, polysaccharides, iron uptake systems, and the type secretion systems III–V were observed in just some species. Likewise, a comparison of gene clusters encoding antimicrobial compounds put in evidence for high conservation of carotovoricin, whereas a few species possessed the phenazine, carbapenem, and carocins. Moreover, three clustered regularly interspaced short palindromic repeats-Cas (CRISPR-Cas) systems: I-E, I-F, and III-A were identified. Surrounding some CRISPR-Cas regions, different toxin and antitoxin systems were found, which suggests bacterial suicide in the case of an immune system failure. Multiple whole-genome alignments shed light on to the presence of a novel cellobiose phosphotransferase system (PTS) exclusive to P. parmenteri, and an unreported T5SS conserved in almost all species. Several regions that were associated with virulence, microbe antagonism, and adaptive immune systems were predicted within genomic islands, which underscored the essential role that horizontal gene transfer has imparted in the dynamic evolution and speciation of Pectobacterium species. Overall, the results decipher the different strategies that each species has developed to infect their hosts, outcompete for food resources, and defend against bacteriophages. Our investigation provides novel genetic insights that will assist in understanding the pathogenic lifestyle of Pectobacterium, a genus that jeopardizes the agriculture sustainability of important crops worldwide. Full article
(This article belongs to the Section Plant Pathogens)
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14 pages, 1981 KB  
Article
LmxM.22.0250-Encoded Dual Specificity Protein/Lipid Phosphatase Impairs Leishmania mexicana Virulence In Vitro
by Natalya Kraeva, Tereza Leštinová, Aygul Ishemgulova, Karolina Majerová, Anzhelika Butenko, Slavica Vaselek, Julia Bespyatykh, Arzuv Charyyeva, Tatiana Spitzová, Alexei Yu. Kostygov, Julius Lukeš, Petr Volf, Jan Votýpka and Vyacheslav Yurchenko
Pathogens 2019, 8(4), 241; https://doi.org/10.3390/pathogens8040241 - 17 Nov 2019
Cited by 13 | Viewed by 3959
Abstract
Protein phosphorylation/dephosphorylation is an important regulatory mechanism that controls many key physiological processes. Numerous pathogens successfully use kinases and phosphatases to internalize, replicate, and survive, modifying the host′s phosphorylation profile or signal transduction pathways. Multiple phosphatases and kinases from diverse bacterial pathogens have [...] Read more.
Protein phosphorylation/dephosphorylation is an important regulatory mechanism that controls many key physiological processes. Numerous pathogens successfully use kinases and phosphatases to internalize, replicate, and survive, modifying the host′s phosphorylation profile or signal transduction pathways. Multiple phosphatases and kinases from diverse bacterial pathogens have been implicated in human infections before. In this work, we have identified and characterized the dual specificity protein/lipid phosphatase LmDUSP1 as a novel virulence factor governing Leishmania mexicana infection. The LmDUSP1-encoding gene (LmxM.22.0250 in L. mexicana) has been acquired from bacteria via horizontal gene transfer. Importantly, its orthologues have been associated with virulence in several bacterial species, such as Mycobacterium tuberculosis and Listeria monocytogenes. Leishmania mexicana with ablated LmxM.22.0250 demonstrated severely attenuated virulence in the experimental infection of primary mouse macrophages, suggesting that this gene facilitates Leishmania pathogenicity in vertebrates. Despite significant upregulation of LmxM.22.0250 expression in metacyclic promastigotes, its ablation did not affect the ability of mutant cells to differentiate into virulent stages in insects. It remains to be further investigated which specific biochemical pathways involve LmDUSP1 and how this facilitates the parasite′s survival in the host. One of the interesting possibilities is that LmDUSP1 may target host′s substrate(s), thereby affecting its signal transduction pathways. Full article
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12 pages, 1743 KB  
Article
A Single and Un-Adjuvanted Dose of a Chimpanzee Adenovirus-Vectored Vaccine against Chikungunya Virus Fully Protects Mice from Lethal Disease
by Rafael Kroon Campos, Lorena Preciado-Llanes, Sasha R. Azar, Cesar Lopez-Camacho, Arturo Reyes-Sandoval and Shannan L. Rossi
Pathogens 2019, 8(4), 231; https://doi.org/10.3390/pathogens8040231 - 12 Nov 2019
Cited by 30 | Viewed by 6122
Abstract
The mosquito-borne chikungunya virus (CHIKV) has become a major global health problem. Upon infection, chikungunya fever (CHIKF) can result in long-term joint pain and arthritis, and despite intense research, no licensed vaccine for CHIKV is available. We have developed two recombinant chimpanzee adenovirus-vectored [...] Read more.
The mosquito-borne chikungunya virus (CHIKV) has become a major global health problem. Upon infection, chikungunya fever (CHIKF) can result in long-term joint pain and arthritis, and despite intense research, no licensed vaccine for CHIKV is available. We have developed two recombinant chimpanzee adenovirus-vectored vaccines (ChAdOx1) that induce swift and robust anti-CHIKV immune responses with a single dose, without the need for adjuvants or booster vaccines. Here, we report the vaccines’ protective efficacies against CHIKV infection in a lethal A129 mouse model. Our results indicate that a single, un-adjuvanted ChAdOx1 Chik or ChAdOx1 Chik ΔCap dose provided complete protection against a lethal virus challenge and prevented CHIKV-associated severe inflammation. These candidate vaccines supported survival equal to the attenuated 181/25 CHIKV reference vaccine but without the vaccine-related side effects, such as weight loss. Vaccination with either ChAdOx1 Chik or ChAdOx1 Chik ΔCap resulted in high titers of neutralizing antibodies that are associated with protection, indicating that the presence of the capsid within the vaccine construct may not be essential to afford protection under the conditions tested. We conclude that both replication-deficient ChAdOx1 Chik vaccines are safe even when used in A129 mice and afford complete protection from a lethal challenge. Full article
(This article belongs to the Special Issue Vaccines against Alphaviruses and Flaviviruses)
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9 pages, 1357 KB  
Review
West Nile Virus Induced Cell Death in the Central Nervous System
by Bi-Hung Peng and Tian Wang
Pathogens 2019, 8(4), 215; https://doi.org/10.3390/pathogens8040215 - 1 Nov 2019
Cited by 34 | Viewed by 5253
Abstract
West Nile virus (WNV), a mosquito-borne, single-stranded flavivirus, has caused annual outbreaks of viral encephalitis in the United States since 1999. The virus induces acute infection with a clinical spectrum ranging from a mild flu-like febrile symptom to more severe neuroinvasive conditions, including [...] Read more.
West Nile virus (WNV), a mosquito-borne, single-stranded flavivirus, has caused annual outbreaks of viral encephalitis in the United States since 1999. The virus induces acute infection with a clinical spectrum ranging from a mild flu-like febrile symptom to more severe neuroinvasive conditions, including meningitis, encephalitis, acute flaccid paralysis, and death. Some WNV convalescent patients also developed long-term neurological sequelae. Neither the treatment of WNV infection nor an approved vaccine is currently available for humans. Neuronal death in the central nervous system (CNS) is a hallmark of WNV-induced meningitis and encephalitis. However, the underlying mechanisms of WNV-induced neuronal damage are not well understood. In this review, we discuss current findings from studies of WNV infection in vitro in the CNS resident cells and the in vivo animal models, and provide insights into WNV-induced neuropathogenesis. Full article
(This article belongs to the Special Issue Pathogenesis of West Nile Virus)
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12 pages, 5962 KB  
Article
Zebrafish are Resistant to Staphylococcus aureus Endophthalmitis
by Frank Mei, Matthew Rolain, Xiao Yi Zhou, Pawan Kumar Singh, Ryan Thummel and Ashok Kumar
Pathogens 2019, 8(4), 207; https://doi.org/10.3390/pathogens8040207 - 26 Oct 2019
Cited by 6 | Viewed by 5840
Abstract
Gram-positive bacteria remain the leading cause of endophthalmitis, a blinding infectious disease of the eye. Murine models have been widely used for understanding the pathogenesis of bacterial endophthalmitis. In this study, we sought to develop an alternative zebrafish (Danio rerio) model [...] Read more.
Gram-positive bacteria remain the leading cause of endophthalmitis, a blinding infectious disease of the eye. Murine models have been widely used for understanding the pathogenesis of bacterial endophthalmitis. In this study, we sought to develop an alternative zebrafish (Danio rerio) model for Staphylococcus aureus and compare the disease pathobiology to a murine model. Endophthalmitis was induced in zebrafish and C57BL/6 mice through the intravitreal injection of S. aureus. Disease progression was monitored by assessing corneal haze, opacity, bacterial burden, and retinal histology. Our results demonstrated that, unlike the murine models, zebrafish maintained ocular integrity, corneal transparency, and retinal architecture. We found that the zebrafish was capable of clearing S. aureus from the eye via transport through retinal vessels and the optic nerve and by mounting a monocyte/macrophage response beginning at 8 hour post-infection (hpi). The bacterial burden increased up to 8 hpi and significantly decreased thereafter. An assessment of the innate retinal response revealed the induced expression of Il-1β and Il-6 transcripts. Collectively, our study shows that unlike the murine model, zebrafish do not develop endophthalmitis and rapidly clear the pathogen. Hence, a better understanding of the zebrafish protective ocular innate response may provide new insights into the pathobiology of bacterial endophthalmitis. Full article
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11 pages, 1929 KB  
Case Report
Taxonomical and Functional Assessment of the Endometrial Microbiota in A Context of Recurrent Reproductive Failure: A Case Report
by Iolanda Garcia-Grau, David Perez-Villaroya, Davide Bau, Marta Gonzalez-Monfort, Felipe Vilella, Inmaculada Moreno and Carlos Simon
Pathogens 2019, 8(4), 205; https://doi.org/10.3390/pathogens8040205 - 24 Oct 2019
Cited by 42 | Viewed by 7181
Abstract
Investigation of the microbial community in the female reproductive tract has revealed that the replacement of a community dominated by Lactobacillus with pathogenic bacteria may be associated with implantation failure or early spontaneous abortion in patients undergoing assisted reproductive technology (ART) treatment. Herein [...] Read more.
Investigation of the microbial community in the female reproductive tract has revealed that the replacement of a community dominated by Lactobacillus with pathogenic bacteria may be associated with implantation failure or early spontaneous abortion in patients undergoing assisted reproductive technology (ART) treatment. Herein we describe taxonomically and functionally the endometrial microbiome of an infertile patient with repeated reproductive failures (involving an ectopic pregnancy and two clinical miscarriages). The microbiological follow-up is presented over 18-month in which the microbiota was evaluated in six endometrial fluid samples. The microbial profile of 16S rRNA gene sequencing showed a persistent infection with Gardnerella and other bacterial taxa such as Atopobium and Bifidobacterium. In addition, taxonomic and functional analysis by whole metagenome sequencing in the endometrial fluid sample collected before one clinical miscarriage suggested the presence of multiple Gardnerella vaginalis clades with a greater abundance of clade 4, usually associated with metronidazole resistance. These results revealed a persistent G. vaginalis endometrial colonization presenting genetic features consistent with antimicrobial resistance, biofilm formation, and other virulence factors, which could be related to the reproductive failure observed. Full article
(This article belongs to the Section Human Pathogens)
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34 pages, 4778 KB  
Article
An Acute Stress Model in New Zealand White Rabbits Exhibits Altered Immune Response to Infection with West Nile Virus
by Willy W. Suen, Mitchell Imoda, Albert W. Thomas, Nur N.B.M. Nasir, Nawaporn Tearnsing, Wenqi Wang and Helle Bielefeldt-Ohmann
Pathogens 2019, 8(4), 195; https://doi.org/10.3390/pathogens8040195 - 18 Oct 2019
Cited by 5 | Viewed by 3751
Abstract
The immune competence of an individual is a major determinant of morbidity in West Nile virus (WNV)-infection. Previously, we showed that immunocompetent New Zealand White rabbits (NZWRs; Oryctolagus cuniculus) are phenotypically resistant to WNV-induced disease, thus presenting a suitable model for study [...] Read more.
The immune competence of an individual is a major determinant of morbidity in West Nile virus (WNV)-infection. Previously, we showed that immunocompetent New Zealand White rabbits (NZWRs; Oryctolagus cuniculus) are phenotypically resistant to WNV-induced disease, thus presenting a suitable model for study of virus-control mechanisms. The current study used corticosteroid-treated NZWRs to model acute “stress”-related immunosuppression. Maximal effects on immune parameters were observed on day 3 post dexamethasone-treatment (pdt). However, contrary to our hypothesis, intradermal WNV challenge at this time pdt produced significantly lower viremia 1 day post-infection (dpi) compared to untreated controls, suggestive of changes to antiviral control mechanisms. To examine this further, RNAseq was performed on RNA extracted from draining lymph node—the first site of virus replication and immune detection. Unaffected by dexamethasone-treatment, an early antiviral response, primarily via interferon (IFN)-I, and induction of a range of known and novel IFN-stimulated genes, was observed. However, treatment was associated with expression of a different repertoire of IFN-α-21-like and IFN-ω-1-like subtypes on 1 dpi, which may have driven the different chemokine response on 3 dpi. Ongoing expression of Toll-like receptor-3 and transmembrane protein-173/STING likely contributed to signaling of the treatment-independent IFN-I response. Two novel genes (putative HERC6 and IFIT1B genes), and the SLC16A5 gene were also highlighted as important component of the transcriptomic response. Therefore, the current study shows that rabbits are capable of restricting WNV replication and dissemination by known and novel robust antiviral mechanisms despite environmental challenges such as stress. Full article
(This article belongs to the Special Issue Pathogenesis of West Nile Virus)
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9 pages, 2769 KB  
Review
Formation and Maintenance of Tissue Resident Memory CD8+ T Cells after Viral Infection
by David J. Topham, Emma C. Reilly, Kris Lambert Emo and Mike Sportiello
Pathogens 2019, 8(4), 196; https://doi.org/10.3390/pathogens8040196 - 18 Oct 2019
Cited by 9 | Viewed by 4809
Abstract
Tissue resident memory (TRM) CD8 T cells comprise a memory population that forms in peripheral, non-lymphoid tissues after an infection that does not recirculate into the bloodstream or other tissues. TRM cells often recognize conserved peptide epitopes shared among different [...] Read more.
Tissue resident memory (TRM) CD8 T cells comprise a memory population that forms in peripheral, non-lymphoid tissues after an infection that does not recirculate into the bloodstream or other tissues. TRM cells often recognize conserved peptide epitopes shared among different strains of a pathogen and so offer a protective role upon secondary encounter with the same or related pathogens. Several recent studies have begun to shed light on the intrinsic and extrinsic factors regulating TRM. In addition, work is being done to understand how canonical “markers” of TRM actually affect the function of these cells. Many of these markers regulate the generation or persistence of these TRM cells, an important point of study due to the differences in persistence of TRM between tissues, which may impact future vaccine development to cater towards these important differences. In this review, we will discuss recent advances in TRM biology that may lead to strategies designed to promote this important protective immune subset. Full article
(This article belongs to the Special Issue Influenza Virus and Vaccination)
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21 pages, 861 KB  
Review
Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications
by Fengwei Bai, E. Ashley Thompson, Parminder J. S. Vig and A. Arturo Leis
Pathogens 2019, 8(4), 193; https://doi.org/10.3390/pathogens8040193 - 16 Oct 2019
Cited by 82 | Viewed by 16335
Abstract
West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States [...] Read more.
West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States in the New York City outbreak of 1999. Despite 20 years of intensive laboratory and clinical research, there are still no approved vaccines or antivirals available for human use. However, rapid progress has been made in both understanding the pathogenesis of WNV and treatment in clinical practices. This review summarizes our current understanding of WNV infection in terms of human clinical manifestations, host immune responses, neuroinvasion, and therapeutic interventions. Full article
(This article belongs to the Special Issue Pathogenesis of West Nile Virus)
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13 pages, 2346 KB  
Article
Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins
by Markus Hoffmann, Svenja Victoria Kaufmann, Carina Fischer, Wiebke Maurer, Anna-Sophie Moldenhauer and Stefan Pöhlmann
Pathogens 2019, 8(4), 192; https://doi.org/10.3390/pathogens8040192 - 15 Oct 2019
Cited by 4 | Viewed by 4448
Abstract
Ebola virus (EBOV) infection can cause severe and frequently fatal disease in human patients. The EBOV glycoprotein (GP) mediates viral entry into host cells. For this, GP depends on priming by the pH-dependent endolysosomal cysteine proteases cathepsin B (CatB) and, to a lesser [...] Read more.
Ebola virus (EBOV) infection can cause severe and frequently fatal disease in human patients. The EBOV glycoprotein (GP) mediates viral entry into host cells. For this, GP depends on priming by the pH-dependent endolysosomal cysteine proteases cathepsin B (CatB) and, to a lesser degree, cathepsin L (CatL), at least in most cell culture systems. However, there is limited information on whether and how EBOV-GP can acquire resistance to CatB/L inhibitors. Here, we addressed this question using replication-competent vesicular stomatitis virus bearing EBOV-GP. Five passages of this virus in the presence of the CatB/CatL inhibitor MDL28170 were sufficient to select resistant viral variants and sequencing revealed that all GP sequences contained a V37A mutation, which, in the context of native GP, is located in the base of the GP surface unit. In addition, some GP sequences harbored mutation S195R in the receptor-binding domain. Finally, mutational analysis demonstrated that V37A but not S195R conferred resistance against MDL28170 and other CatB/CatL inhibitors. Collectively, a single amino acid substitution in GP is sufficient to confer resistance against CatB/CatL inhibitors, suggesting that usage of CatB/CatL inhibitors for antiviral therapy may rapidly select for resistant viral variants. Full article
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17 pages, 2478 KB  
Article
Genomic Epidemiology of Streptococcus suis Sequence Type 7 Sporadic Infections in the Guangxi Zhuang Autonomous Region of China
by Mingliu Wang, Pengcheng Du, Jianping Wang, Ruiting Lan, Jun Huang, Ming Luo, Yan Jiang, Jun Zeng, Yi Quan, Zhaohui Shi and Han Zheng
Pathogens 2019, 8(4), 187; https://doi.org/10.3390/pathogens8040187 - 12 Oct 2019
Cited by 26 | Viewed by 4467
Abstract
Streptococcus suis is an important zoonotic pathogen. Serotype 2 and sequence type (ST) 1 are the most frequently reported strains in both infected humans and pigs. ST7 is only endemic to China, and it was responsible for outbreaks in 1998 and 2005 in [...] Read more.
Streptococcus suis is an important zoonotic pathogen. Serotype 2 and sequence type (ST) 1 are the most frequently reported strains in both infected humans and pigs. ST7 is only endemic to China, and it was responsible for outbreaks in 1998 and 2005 in China. In the present study, 38 sporadic ST7 S. suis strains, which mostly caused sepsis, were collected from patients in the Guangxi Zhuang Autonomous Region (GX) between 2007 and 2018. Of 38 sporadic ST7 strains, serotype 14 was the most frequent (27 strains, 71.1%), followed by serotype 2 (11 strains, 28.9%). The phylogenetic structure of the ST7 population, including epidemic and sporadic ST7 strains, was constructed using mutational single-nucleotide polymorphisms (SNPs). High diversity within the ST7 population was revealed and divided into five lineages. Only one sporadic ST7 strain, GX14, from a Streptococcal toxic-shock-like syndrome (STSLS) patient was clustered into the same lineage as the epidemic strains. GX14 and the epidemic strains diverged in 1974. The sporadic ST7 strains of GX were mainly clustered into lineage 5, which emerged in 1980. Comparing to genome of epidemic strain, the major differences in genome of sporadic ST7 strains of GX was the absence of 89 kb pathogenicity island (PAI) specific to epidemic strain and insertion of 128 kb ICE_phage tandem MGE or ICE portion of the MGE. These mobile elements play a significant role in the horizontal transfer of antibiotic resistance genes in sporadic ST7 strains. Our results enhanced the understanding of the evolution of the ST7 strains and their ability to cause life-threatening infections in humans. Full article
(This article belongs to the Special Issue Update on Streptococcus suis Research and Prevention in the Era of Antibiotic Restriction - 4th International Workshop on Streptococcus suis)
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15 pages, 3967 KB  
Article
Whole Transcriptome Analyses Reveal Differential mRNA and microRNA Expression Profiles in Primary Human Dermal Fibroblasts Infected with Clinical or Vaccine Strains of Varicella Zoster Virus
by Soo-Jin Oh, Sooyeon Lim, Moon Jung Song, Jin Hyun Ahn, Chan Hee Lee and Ok Sarah Shin
Pathogens 2019, 8(4), 183; https://doi.org/10.3390/pathogens8040183 - 10 Oct 2019
Cited by 15 | Viewed by 4633
Abstract
Licensed live attenuated vaccines have been developed to prevent varicella zoster virus (VZV) infection, which causes chickenpox and shingles. The genomic sequences of both clinical- and vaccine-derived VZV strains have been analyzed previously. To further characterize the molecular signatures and complexity of wildtype [...] Read more.
Licensed live attenuated vaccines have been developed to prevent varicella zoster virus (VZV) infection, which causes chickenpox and shingles. The genomic sequences of both clinical- and vaccine-derived VZV strains have been analyzed previously. To further characterize the molecular signatures and complexity of wildtype (clinical) versus attenuated (vaccine-derived) VZV-mediated host cellular responses, we performed high-throughput next generation sequencing to quantify and compare the expression patterns of mRNAs and microRNAs (miRNAs) in primary human dermal fibroblasts (HDFs) infected with wildtype (YC01 low passage) and attenuated (YC01 high passage, SuduVax, and VarilRix) VZV strains. 3D-multidimensional scaling of the differentially expressed genes demonstrated the distinct grouping of wildtype and attenuated strains. In particular, we observed that HDFs infected with attenuated strains had more differentially expressed genes (DEGs) involved in the retinoic-acid inducible gene–I-like receptor and interferon-mediated signaling pathways compared with wildtype strains. Additionally, miRNA expression patterns were profiled following the infection of HDFs with VZV. Small RNA sequencing identified that several miRNAs were upregulated, including miR-146a-5p, which has been associated with other herpesvirus infections, whereas let-7a-3p was downregulated in both wildtype and attenuated VZV-infected cells. This study identified genes and miRNAs that may be essential in VZV pathogenesis. Full article
(This article belongs to the Special Issue Human Herpesviruses: Diversity and Disease)
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22 pages, 906 KB  
Review
Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans
by Aitor Nogales and Marta L. DeDiego
Pathogens 2019, 8(4), 168; https://doi.org/10.3390/pathogens8040168 - 30 Sep 2019
Cited by 28 | Viewed by 8840
Abstract
A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can [...] Read more.
A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness. Full article
(This article belongs to the Special Issue Influenza Virus and Vaccination)
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13 pages, 3321 KB  
Article
Atypical Dermatophytosis in 12 North American Porcupines (Erethizon dorsatum) from the Northeastern United States 2010–2017
by David B. Needle, Robert Gibson, Nicholas A. Hollingshead, Inga F. Sidor, Nicholas J. Marra, Derek Rothenheber, Anil J. Thachil, Bryce J. Stanhope, Brian A. Stevens, Julie C. Ellis, Shelley Spanswick, Maureen Murray and Laura B. Goodman
Pathogens 2019, 8(4), 171; https://doi.org/10.3390/pathogens8040171 - 30 Sep 2019
Cited by 9 | Viewed by 5288
Abstract
Twelve wild North American porcupines (Erethizon dorsatum) out of a total of 44 of this species examined in an 8-year period were diagnosed with dermatopathies while being cared for at two wildlife rehabilitation clinics. Biopsy and necropsy were performed on seven [...] Read more.
Twelve wild North American porcupines (Erethizon dorsatum) out of a total of 44 of this species examined in an 8-year period were diagnosed with dermatopathies while being cared for at two wildlife rehabilitation clinics. Biopsy and necropsy were performed on seven and five animals, respectively. Atypical dermatophytosis was diagnosed in all cases. Lesions consisted of diffuse severe epidermal hyperkeratosis and mild hyperplasia with mild lymphoplasmacytic dermatitis and no folliculitis. Dermatophytes were noted histologically as hyphae and spores in hair shafts, and follicular and epidermal keratin. Trichophyton sp. was grown in 5/6 animals where culture was performed, with a molecular diagnosis of Arthroderma benhamiae/Trichophyton mentagrophytes in these five cases. Metagenomic analysis of formalin-fixed paraffin-embedded tissue samples from three cases identified fungi from 17 orders in phyla Basidiomycota and Ascomycota. Alteration of therapy from ketaconazole, which was unsuccessful in four out of five early cases, to terbinafine or nitraconazole led to the resolution of disease and recovery to release in four subsequent animals. In all, six animals were euthanized or died due to dermatopathy, no cases resolved spontaneously, and six cases were resolved with therapy. The work we present demonstrates an atypical lesion and anatomical distribution due to dermatophytosis in a series of free-ranging wild porcupines and the successful development of novel techniques for extracting and sequencing nucleic acids from fungus in archival formalin-fixed paraffin-embedded animal tissue. Full article
(This article belongs to the Section Animal Pathogens)
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13 pages, 1114 KB  
Review
Role of Memory B Cells in Hemagglutinin-Specific Antibody Production Following Human Influenza A Virus Infection
by Mark Y. Sangster, Phuong Q. T. Nguyen and David J. Topham
Pathogens 2019, 8(4), 167; https://doi.org/10.3390/pathogens8040167 - 28 Sep 2019
Cited by 21 | Viewed by 7598
Abstract
When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against [...] Read more.
When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against the conserved HA stalk provide broader but less potent protection. In this review, we provide a comprehensive picture of an adult’s HA-specific antibody response to influenza virus infection. The process is followed from preexisting HA-specific MBC activation and rapid production of anti-HA antibodies, through to germinal center seeding and adaptation of the response to novel features of the HA. A major focus of the review is the role of competition between preexisting MBCs in determining the character of the HA-reactive antibody response. HA novelty modifies this competition and can shift the response from the immunodominant head to the stalk. We suggest that antibodies resulting from preexisting MBC activation are important regulators of anti-HA antibody production and play a role in positive selection of germinal center B cells reactive to novel HA epitopes. Our review also considers the role of MBCs in the effects of early-life imprinting on HA head- and stalk-specific antibody responses to influenza infection. An understanding of the processes described in this review will guide development of vaccination strategies that provide broadly effective protection. Full article
(This article belongs to the Special Issue Influenza Virus and Vaccination)
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15 pages, 947 KB  
Article
Prevalence of Various Vaccine Candidate Proteins in Clinical Isolates of Streptococcus pneumoniae: Characterization of the Novel Pht Fusion Proteins PhtA/B and PhtA/D
by Mitsuyo Kawaguchiya, Noriko Urushibara, Meiji Soe Aung, Masaaki Shinagawa, Satoshi Takahashi and Nobumichi Kobayashi
Pathogens 2019, 8(4), 162; https://doi.org/10.3390/pathogens8040162 - 24 Sep 2019
Cited by 10 | Viewed by 3740
Abstract
Pneumococcal proteins unrelated to serotypes are considered to be candidates of antigens in next-generation vaccines. In the present study, the prevalence of vaccine candidate protein genes, along with serotypes and antimicrobial resistance determinants, was investigated in a total of 57 isolates obtained from [...] Read more.
Pneumococcal proteins unrelated to serotypes are considered to be candidates of antigens in next-generation vaccines. In the present study, the prevalence of vaccine candidate protein genes, along with serotypes and antimicrobial resistance determinants, was investigated in a total of 57 isolates obtained from a tertiary care hospital in Japan. All of the pediatric isolates and 76.6% of the adult isolates did not belong to PCV13 (a 13-valent pneumococcal conjugate vaccine) serotypes, and 70.2% of all isolates showed multidrug resistance. All of the isolates had ply, pavA, nanA, and nanB, and high prevalence was noted for the pspA and pspC genes (96.5% and 78.9%, respectively). Detection rates for the pneumococcal histidine triad protein (Pht) genes phtA, phtB, phtD, and phtE were 49.1%, 26.3%, 61.4%, and 100%, respectively. Two fusion-type genes, phtA/B and phtA/D, were identified, with a prevalence of 36.9% and 14.0%, respectively. These fusion types showed 78.1–90.0% nucleotide sequence identity with phtA, phtB, and phtD. The most prevalent pht profile was phtA + phtD + phtE (26.3%), followed by phtA/B + phtE (19.3%) and phtA/B + phtD + phtE (17.5%), while pht profiles including phtD and/or phtA/phtD were found in 71.9% of isolates. The present study revealed the presence of two fusion types of Pht and their unexpectedly high prevalence. These fusion types, as well as PhtA and PhtB, contained sequences similar to the B cell epitopes that have been previously reported for PhtD. Full article
(This article belongs to the Section Human Pathogens)
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12 pages, 4546 KB  
Article
New Taxon-Specific Heterobasidion PCR Primers Detect and Differentiate North American Heterobasidion spp. in Various Substrates and Led to the Discovery of Heterobasidion irregulare in British Columbia, Canada
by Simon Francis Shamoun, Craig Hammett, Grace Sumampong, Xiang Li and Matteo Garbelotto
Pathogens 2019, 8(3), 156; https://doi.org/10.3390/pathogens8030156 - 18 Sep 2019
Cited by 6 | Viewed by 5299
Abstract
Heterobasidion annosum sensu lato is a species complex of pathogenic white-rot wood decay fungi which cause root and butt rot in conifer and hardwood species across the Northern hemisphere. Annual losses to forest managers are valued in the billions of dollars, due to [...] Read more.
Heterobasidion annosum sensu lato is a species complex of pathogenic white-rot wood decay fungi which cause root and butt rot in conifer and hardwood species across the Northern hemisphere. Annual losses to forest managers are valued in the billions of dollars, due to tree mortality, reduction in timber yield, and wood decay. In North America, H. irregulare and H. occidentale have a partially overlapping host and geographic range, cause similar disease symptoms and produce similar fruiting bodies, making discrimination between the two of them often difficult. We developed two sets of primers that bind specifically to conserved, but species-specific portions of glyceraldehyde 3-phosphate dehydrogenase and elongation factor 1α alleles. The method is sensitive enough to detect either species from infected wood. Analysis of North American isolates has further clarified the distribution of both species on this continent, including the detection of H. irregulare for the first time on ponderosa pine (Pinus ponderosa) and eastern white pine (Pinus strobus) in British Columbia. This method has the potential to be a valuable tool for the detection of the pathogen in exported/imported wood products, as well as for the further identification and assessment of the distribution of North American Heterobasidion species. Full article
(This article belongs to the Section Plant Pathogens)
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10 pages, 1001 KB  
Review
Role of Endoplasmic Reticulum-Associated Proteins in Flavivirus Replication and Assembly Complexes
by Hussin A. Rothan and Mukesh Kumar
Pathogens 2019, 8(3), 148; https://doi.org/10.3390/pathogens8030148 - 12 Sep 2019
Cited by 36 | Viewed by 7162
Abstract
Flavivirus replication in host cells requires the formation of replication and assembly complexes on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. These complexes consist of an ER membrane, viral proteins, and host proteins. Genome-wide investigations have identified a number of ER [...] Read more.
Flavivirus replication in host cells requires the formation of replication and assembly complexes on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. These complexes consist of an ER membrane, viral proteins, and host proteins. Genome-wide investigations have identified a number of ER multiprotein complexes as vital factors for flavivirus replication. The detailed mechanisms of the role of ER complexes in flavivirus replication are still largely elusive. This review highlights the fact that the ER multiprotein complexes are crucial for the formation of flavivirus replication and assembly complexes, and the ER complexes could be considered as a target for developing successful broad-spectrum anti-flavivirus drugs. Full article
(This article belongs to the Special Issue Current Advances in Flavivirus Research)
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14 pages, 3346 KB  
Article
A Single Dose of Modified Vaccinia Ankara Expressing Lassa Virus-like Particles Protects Mice from Lethal Intra-cerebral Virus Challenge
by Maria S. Salvato, Arban Domi, Camila Guzmán-Cardozo, Sandra Medina-Moreno, Juan Carlos Zapata, Haoting Hsu, Nathanael McCurley, Rahul Basu, Mary Hauser, Michael Hellerstein and Farshad Guirakhoo
Pathogens 2019, 8(3), 133; https://doi.org/10.3390/pathogens8030133 - 28 Aug 2019
Cited by 27 | Viewed by 9914
Abstract
Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report [...] Read more.
Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus. Full article
(This article belongs to the Special Issue Lassa Fever: Viral Replication, Disease Pathogenesis, and Host Immune Modulations)
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28 pages, 1438 KB  
Review
Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome
by Israr Khan, Naeem Ullah, Lajia Zha, Yanrui Bai, Ashiq Khan, Tang Zhao, Tuanjie Che and Chunjiang Zhang
Pathogens 2019, 8(3), 126; https://doi.org/10.3390/pathogens8030126 - 13 Aug 2019
Cited by 621 | Viewed by 35432
Abstract
Inflammatory bowel disease (IBD) is a chronic complex inflammatory gut pathological condition, examples of which include Crohn’s disease (CD) and ulcerative colitis (UC), which is associated with significant morbidity. Although the etiology of IBD is unknown, gut microbiota alteration (dysbiosis) is considered a [...] Read more.
Inflammatory bowel disease (IBD) is a chronic complex inflammatory gut pathological condition, examples of which include Crohn’s disease (CD) and ulcerative colitis (UC), which is associated with significant morbidity. Although the etiology of IBD is unknown, gut microbiota alteration (dysbiosis) is considered a novel factor involved in the pathogenesis of IBD. The gut microbiota acts as a metabolic organ and contributes to human health by performing various physiological functions; deviation in the gut flora composition is involved in various disease pathologies, including IBD. This review aims to summarize the current knowledge of gut microbiota alteration in IBD and how this contributes to intestinal inflammation, as well as explore the potential role of gut microbiota-based treatment approaches for the prevention and treatment of IBD. The current literature has clearly demonstrated a perturbation of the gut microbiota in IBD patients and mice colitis models, but a clear causal link of cause and effect has not yet been presented. In addition, gut microbiota-based therapeutic approaches have also shown good evidence of their effects in the amelioration of colitis in animal models (mice) and IBD patients, which indicates that gut flora might be a new promising therapeutic target for the treatment of IBD. However, insufficient data and confusing results from previous studies have led to a failure to define a core microbiome associated with IBD and the hidden mechanism of pathogenesis, which suggests that well-designed randomized control trials and mouse models are required for further research. In addition, a better understanding of this ecosystem will also determine the role of prebiotics and probiotics as therapeutic agents in the management of IBD. Full article
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11 pages, 6927 KB  
Article
In Vitro Activity of Statins against Naegleria fowleri
by Aitor Rizo-Liendo, Ines Sifaoui, María Reyes-Batlle, Olfa Chiboub, Rubén L. Rodríguez-Expósito, Carlos J. Bethencourt-Estrella, Desirée San Nicolás-Hernández, Edyta B. Hendiger, Atteneri López-Arencibia, Pedro Rocha-Cabrera, José E. Piñero and Jacob Lorenzo-Morales
Pathogens 2019, 8(3), 122; https://doi.org/10.3390/pathogens8030122 - 8 Aug 2019
Cited by 29 | Viewed by 5825
Abstract
Naegleria fowleri causes a deadly disease called primary amoebic meningoencephalitis (PAM). Even though PAM is still considered a rare disease, the number of reported cases worldwide has been increasing each year. Among the factors to be considered for this, awareness about this disease, [...] Read more.
Naegleria fowleri causes a deadly disease called primary amoebic meningoencephalitis (PAM). Even though PAM is still considered a rare disease, the number of reported cases worldwide has been increasing each year. Among the factors to be considered for this, awareness about this disease, and also global warming, as these amoebae thrive in warm water bodies, seem to be the key factors. Until present, no fully effective drugs have been developed to treat PAM, and the current options are amphotericin B and miltefosine, which present side effects such as liver and kidney toxicity. Statins are able to inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is a key enzyme for the synthesis of ergosterol of the cell membrane of these amoebae. Therefore, the in vitro activity of a group of statins was tested in this study against two types of strains of Naegleria fowleri. The obtained results showed that fluvastatin was the most effective statin tested in this study and was able to eliminate these amoebae at concentrations of 0.179 ± 0.078 to 1.682 ± 0.775 µM depending on the tested strain of N. fowleri. Therefore, fluvastatin could be a potential novel therapeutic agent against this emerging pathogen. Full article
(This article belongs to the Special Issue Emerging Parasitic Protozoa)
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11 pages, 2360 KB  
Article
Genetic Characterization of Chikungunya Virus in Field-Caught Aedes aegypti Mosquitoes Collected during the Recent Outbreaks in 2019, Thailand
by Proawpilart Intayot, Atchara Phumee, Rungfar Boonserm, Sriwatapron Sor-suwan, Rome Buathong, Supaporn Wacharapluesadee, Narisa Brownell, Yong Poovorawan and Padet Siriyasatien
Pathogens 2019, 8(3), 121; https://doi.org/10.3390/pathogens8030121 - 2 Aug 2019
Cited by 28 | Viewed by 6476
Abstract
Chikungunya virus (CHIKV) is a mosquito-borne virus belonging to the genus Alphavirus. The virus is transmitted to humans by the bite of infected female Aedes mosquitoes, primarily Aedes aegypti. CHIKV infection is spreading worldwide, and it periodically sparks new outbreaks. There [...] Read more.
Chikungunya virus (CHIKV) is a mosquito-borne virus belonging to the genus Alphavirus. The virus is transmitted to humans by the bite of infected female Aedes mosquitoes, primarily Aedes aegypti. CHIKV infection is spreading worldwide, and it periodically sparks new outbreaks. There are no specific drugs or effective vaccines against CHIKV. The interruption of pathogen transmission by mosquito control provides the only effective approach to the control of CHIKV infection. Many studies have shown that CHIKV can be transmitted among the Ae. aegypti through vertical transmission. The previous chikungunya fever outbreaks in Thailand during 2008–2009 were caused by CHIKV, the East/Central/South African (ECSA) genotype. Recently, there have been 3794 chikungunya cases in 27 provinces reported by the Bureau of Epidemiology of Health Ministry, Thailand during 1 January–16 June 2019; however, the cause of the re-emergence of CHIKV outbreaks is uncertain. Therefore, the aims of this study were to detect and analyze the genetic diversity of CHIKV infection in field-caught mosquitoes. Both female and male Ae. aegypti were collected from endemic areas of Thailand, and CHIKV detection was done by using E1-nested RT-PCR and sequencing analysis. A total of 1646 Ae. aegypti samples (900 females and 746 males) were tested. CHIKV was detected in 54 (3.28%) and 14 samples (0.85%) in female and male mosquitoes, respectively. Seventeen samples of female Ae. aegypti collected from the Ubon Ratchathani, Chiang Rai, Chiang Mai, Nakhon Sawan, and Songkhla provinces found mutation at E1: A226V. Interestingly, E1: K211E mutation was observed in 50 samples collected from Nong Khai, Bangkok, Prachuap Khiri Khan, and Krabi. In addition, the phylogenetic tree indicated that CHIKV in Ae. aegypti samples were from the Indian Ocean Clade and East/South African Clade. Both clades belong to the ECSA genotype. The information obtained from this study could be used for prediction, epidemiological study, prevention, and effective vector control of CHIKV. For instance, a novel CHIKV strain found in new areas has the potential to lead to a new outbreak. Health authorities could plan and apply control strategies more effectively given the tools provided by this research. Full article
(This article belongs to the Special Issue Chikungunya Virus Infections)
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17 pages, 9372 KB  
Article
N-acetyl Cysteine Coated Gallium Particles Demonstrate High Potency against Pseudomonas aeruginosa PAO1
by Mikaeel Young, Ali Ozcan, Briana Lee, Tyler Maxwell, Thomas Andl, Parthiban Rajasekaran, Melanie J. Beazley, Laurene Tetard and Swadeshmukul Santra
Pathogens 2019, 8(3), 120; https://doi.org/10.3390/pathogens8030120 - 1 Aug 2019
Cited by 10 | Viewed by 4376
Abstract
Nosocomial infections pose serious health concerns with over 2 million reported annually in the United States. Many of these infections are associated with bacterial resistance to antibiotics and hence, alternative treatments are critically needed. The objective of this study was to assess the [...] Read more.
Nosocomial infections pose serious health concerns with over 2 million reported annually in the United States. Many of these infections are associated with bacterial resistance to antibiotics and hence, alternative treatments are critically needed. The objective of this study was to assess the antimicrobial efficacy of a gallium (Ga)-based particle coated with N-Acetyl Cysteine (Ga-NAC) against Pseudomonas aeruginosa PAO1. Our studies showed the Minimum Inhibitory Concentration (MIC) of PAO1 treated with Ga-NAC was 1 µg/mL. Cytotoxicity of Ga-NAC against multiple cell lines was determined with no cytotoxicity observed up to concentrations of 2000 µg/mL (metal concentration), indicating a high therapeutic window. To elucidate potential antibacterial modes of action, Inductively Coupled Plasma—Mass Spectrometry (ICP-MS), infrared spectroscopy, and atomic force microscopy (AFM) were used. The results suggest improved Ga3+ interaction with PAO1 through Ga-NAC particles. No significant change in cell membrane chemistry or roughening was detected. As cell membrane integrity remained intact, the antimicrobial mode of action was linked to cellular internalization of Ga and subsequent iron metabolic disruption. Furthermore, Ga-NAC inhibited and disrupted biofilms seen with crystal violet assay and microscopy. Our findings suggest the Ga-NAC particle can potentially be used as an alternative to antibiotics for treatment of Pseudomonas aeruginosa infections. Full article
(This article belongs to the Section Vaccines and Therapeutic Developments)
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22 pages, 1738 KB  
Article
Multi-Lineage Evolution in Viral Populations Driven by Host Immune Systems
by Jacopo Marchi, Michael Lässig, Thierry Mora and Aleksandra M. Walczak
Pathogens 2019, 8(3), 115; https://doi.org/10.3390/pathogens8030115 - 29 Jul 2019
Cited by 11 | Viewed by 5060
Abstract
Viruses evolve in the background of host immune systems that exert selective pressure and drive viral evolutionary trajectories. This interaction leads to different evolutionary patterns in antigenic space. Examples observed in nature include the effectively one-dimensional escape characteristic of influenza A and the [...] Read more.
Viruses evolve in the background of host immune systems that exert selective pressure and drive viral evolutionary trajectories. This interaction leads to different evolutionary patterns in antigenic space. Examples observed in nature include the effectively one-dimensional escape characteristic of influenza A and the prolonged coexistence of lineages in influenza B. Here, we use an evolutionary model for viruses in the presence of immune host systems with finite memory to obtain a phase diagram of evolutionary patterns in a two-dimensional antigenic space. We find that, for small effective mutation rates and mutation jump ranges, a single lineage is the only stable solution. Large effective mutation rates combined with large mutational jumps in antigenic space lead to multiple stably co-existing lineages over prolonged evolutionary periods. These results combined with observations from data constrain the parameter regimes for the adaptation of viruses, including influenza. Full article
(This article belongs to the Special Issue Modeling Virus Dynamics and Evolution)
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19 pages, 1158 KB  
Review
Review of Emerging Japanese Encephalitis Virus: New Aspects and Concepts about Entry into the Brain and Inter-Cellular Spreading
by Luis Filgueira and Nils Lannes
Pathogens 2019, 8(3), 111; https://doi.org/10.3390/pathogens8030111 - 26 Jul 2019
Cited by 70 | Viewed by 11629
Abstract
Japanese encephalitis virus (JEV) is an emerging flavivirus of the Asia-Pacific region. More than two billion people live in endemic or epidemic areas and are at risk of infection. Recently, the first autochthonous human case was recorded in Africa, and infected birds have [...] Read more.
Japanese encephalitis virus (JEV) is an emerging flavivirus of the Asia-Pacific region. More than two billion people live in endemic or epidemic areas and are at risk of infection. Recently, the first autochthonous human case was recorded in Africa, and infected birds have been found in Europe. JEV may spread even further to other continents. The first section of this review covers established and new information about the epidemiology of JEV. The subsequent sections focus on the impact of JEV on humans, including the natural course and immunity. Furthermore, new concepts are discussed about JEV’s entry into the brain. Finally, interactions of JEV and host cells are covered, as well as how JEV may spread in the body through latently infected immune cells and cell-to-cell transmission of virions or via other infectious material, including JEV genomic RNA. Full article
(This article belongs to the Section Human Pathogens)
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25 pages, 918 KB  
Review
Airway Epithelial Derived Cytokines and Chemokines and Their Role in the Immune Response to Respiratory Syncytial Virus Infection
by Lena Glaser, Patricia J. Coulter, Michael Shields, Olivier Touzelet, Ultan F. Power and Lindsay Broadbent
Pathogens 2019, 8(3), 106; https://doi.org/10.3390/pathogens8030106 - 19 Jul 2019
Cited by 59 | Viewed by 10990
Abstract
The airway epithelium is the primary target of respiratory syncytial virus infection. It is an important component of the antiviral immune response. It contributes to the recruitment and activation of innate immune cells from the periphery through the secretion of cytokines and chemokines. [...] Read more.
The airway epithelium is the primary target of respiratory syncytial virus infection. It is an important component of the antiviral immune response. It contributes to the recruitment and activation of innate immune cells from the periphery through the secretion of cytokines and chemokines. This paper provides a broad review of the cytokines and chemokines secreted from human airway epithelial cell models during respiratory syncytial virus (RSV) infection based on a comprehensive literature review. Epithelium-derived chemokines constitute most inflammatory mediators secreted from the epithelium during RSV infection. This suggests chemo-attraction of peripheral immune cells, such as monocytes, neutrophils, eosinophils, and natural killer cells as a key function of the epithelium. The reports of epithelium-derived cytokines are limited. Recent research has started to identify novel cytokines, the functions of which remain largely unknown in the wider context of the RSV immune response. It is argued that the correct choice of in vitro models used for investigations of epithelial immune functions during RSV infection could facilitate greater progress in this field. Full article
(This article belongs to the Special Issue Virus-Host Interactions of Respiratory Syncytial Virus (RSV))
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12 pages, 1321 KB  
Review
Persistence of Babesia microti Infection in Humans
by Evan M. Bloch, Sanjai Kumar and Peter J. Krause
Pathogens 2019, 8(3), 102; https://doi.org/10.3390/pathogens8030102 - 17 Jul 2019
Cited by 77 | Viewed by 23149
Abstract
Persistent infection is a characteristic feature of babesiosis, a worldwide, emerging tick-borne disease caused by members of the genus Babesia. Persistence of Babesia infection in reservoir hosts increases the probability of survival and transmission of these pathogens. Laboratory tools to detect Babesia in [...] Read more.
Persistent infection is a characteristic feature of babesiosis, a worldwide, emerging tick-borne disease caused by members of the genus Babesia. Persistence of Babesia infection in reservoir hosts increases the probability of survival and transmission of these pathogens. Laboratory tools to detect Babesia in red blood cells include microscopic detection using peripheral blood smears, nucleic acid detection (polymerase chain reaction and transcription mediated amplification), antigen detection, and antibody detection. Babesia microti, the major cause of human babesiosis, can asymptomatically infect immunocompetent individuals for up to two years. Chronically infected blood donors may transmit the pathogen to another person through blood transfusion. Transfusion-transmitted babesiosis causes severe complications and death in about a fifth of cases. Immunocompromised patients, including those with asplenia, HIV/AIDS, malignancy, or on immunosuppressive drugs, often experience severe disease that may relapse up to two years later despite anti-Babesia therapy. Persistent Babesia infection is promoted by Babesia immune evasive strategies and impaired host immune mechanisms. The health burden of persistent and recrudescent babesiosis can be minimized by development of novel therapeutic measures, such as new anti-parasitic drugs or drug combinations, improved anti-parasitic drug duration strategies, or immunoglobulin preparations; and novel preventive approaches, including early detection methods, tick-avoidance, and blood donor screening. Full article
(This article belongs to the Special Issue Persistence in Babesia)
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12 pages, 683 KB  
Conference Report
Empowering Women: Moving from Awareness to Action at the Immunology of Fungal Infections Gordon Research Conference
by Elizabeth R. Ballou, Sarah L. Gaffen, Neil A. R. Gow and Amy G. Hise
Pathogens 2019, 8(3), 103; https://doi.org/10.3390/pathogens8030103 - 17 Jul 2019
Cited by 2 | Viewed by 5367
Abstract
Despite the high prevalence of women in graduate degree programs and equal or more women earning PhDs, MDs, and MD/PhDs, and despite efforts at individual and institutional levels to promote women in STEM fields, there remains a disparity in pay and academic advancement [...] Read more.
Despite the high prevalence of women in graduate degree programs and equal or more women earning PhDs, MDs, and MD/PhDs, and despite efforts at individual and institutional levels to promote women in STEM fields, there remains a disparity in pay and academic advancement of women. Likewise, there is a paucity of women in top scientific and academic leadership positions. The causes of this gender disparity are complex and multi-factorial and to date no “magic bullet” approach has been successful in changing the landscape for women in academic and scientific fields. In this report we detail our experiences with a novel mechanism for promoting discussion and raising awareness of the challenges of gender disparity in the sciences. The Gordon Research Conferences (GRC) launched the Power Hour at its meetings in 2016: a dedicated, scheduled session held during the scientific meeting to facilitate discussion of challenges specific to women in science. Here we share our experience with hosting the second Power Hour at the 2019 GRC Immunology of Fungal Infections (IFI) meeting held in Galveston, TX. We will discuss the overall structure, key discussion points, and feedback from participants with the aim of supporting future efforts to empower women and underrepresented minority groups in science. Full article
(This article belongs to the Special Issue Immunology of Fungal Infections)
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10 pages, 1909 KB  
Article
Initiated Babesia ovata Sexual Stages under In Vitro Conditions Were Recognized by Anti-CCp2 Antibodies, Showing Changes in the DNA Content by Imaging Flow Cytometry
by Thu-Thuy Nguyen, Minh-Anh Dang-Trinh, Luna Higuchi, Juan Mosqueda, Hassan Hakimi, Masahito Asada, Junya Yamagishi, Rika Umemiya-Shirafuji and Shin-ichiro Kawazu
Pathogens 2019, 8(3), 104; https://doi.org/10.3390/pathogens8030104 - 17 Jul 2019
Cited by 6 | Viewed by 5590
Abstract
Sexual stage induction under in vitro conditions is useful for biological and molecular studies of Babesia parasites. Therefore, in the present study, we induced B. ovata tick stages using the chemical inducers: xanthurenic acid (XA), dithiothreitol (DTT) and tris (2-carboxyethyl) phosphine (TCEP) at [...] Read more.
Sexual stage induction under in vitro conditions is useful for biological and molecular studies of Babesia parasites. Therefore, in the present study, we induced B. ovata tick stages using the chemical inducers: xanthurenic acid (XA), dithiothreitol (DTT) and tris (2-carboxyethyl) phosphine (TCEP) at 27 °C or 37 °C conditions. Cultures at low temperature (27 °C) or treated with XA/TCEP induced a large number of extra-erythrocytic merozoites, which transformed into round shape cells at 12–24 h post-induction (pi). However, typical forms of tick stages (aggregation forms and the spiky forms/ray bodies) were only observed in the cultures treated with 40 mM or 60 mM of DTT during 3–6 h pi. The induced cells were recognized by anti-CCp2 rabbit antisera. DNA content of the cell population treated with 40 mM of DTT was analyzed by imaging flow cytometry at 0, 12 and 48 h pi. The results indicated that the parasite population with diploid-like double DNA content increased at 48 h pi. Our observations on morphological and changes in the DNA content provide useful information for understanding the life cycle of B. ovata under in vitro conditions, which will facilitate further studies on basic biology and the development of transmission blocking vaccines against bovine babesiosis. Full article
(This article belongs to the Special Issue Persistence in Babesia)
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19 pages, 1169 KB  
Review
Bacteriophages in Natural and Artificial Environments
by Steven Batinovic, Flavia Wassef, Sarah A. Knowler, Daniel T.F. Rice, Cassandra R. Stanton, Jayson Rose, Joseph Tucci, Tadashi Nittami, Antony Vinh, Grant R. Drummond, Christopher G. Sobey, Hiu Tat Chan, Robert J. Seviour, Steve Petrovski and Ashley E. Franks
Pathogens 2019, 8(3), 100; https://doi.org/10.3390/pathogens8030100 - 12 Jul 2019
Cited by 182 | Viewed by 20949
Abstract
Bacteriophages (phages) are biological entities that have attracted a great deal of attention in recent years. They have been reported as the most abundant biological entities on the planet and their ability to impact the composition of bacterial communities is of great interest. [...] Read more.
Bacteriophages (phages) are biological entities that have attracted a great deal of attention in recent years. They have been reported as the most abundant biological entities on the planet and their ability to impact the composition of bacterial communities is of great interest. In this review, we aim to explore where phages exist in natural and artificial environments and how they impact communities. The natural environment in this review will focus on the human body, soils, and the marine environment. In these naturally occurring environments there is an abundance of phages suggesting a role in the maintenance of bacterial community homeostasis. The artificial environment focuses on wastewater treatment plants, industrial processes, followed by pharmaceutical formulations. As in natural environments, the existence of bacteria in manmade wastewater treatment plants and industrial processes inevitably attracts phages. The presence of phages in these environments can inhibit the bacteria required for efficient water treatment or food production. Alternatively, they can have a positive impact by eliminating recalcitrant organisms. Finally, we conclude by describing how phages can be manipulated or formulated into pharmaceutical products in the laboratory for use in natural or artificial environments. Full article
(This article belongs to the Special Issue Waterborne Zoonotic Pathogens)
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17 pages, 3660 KB  
Article
Surface Immobilization of Nano-Silver on Polymeric Medical Devices to Prevent Bacterial Biofilm Formation
by Andri K. Riau, Thet T. Aung, Melina Setiawan, Liang Yang, Gary H. F. Yam, Roger W. Beuerman, Subbu S. Venkatraman and Jodhbir S. Mehta
Pathogens 2019, 8(3), 93; https://doi.org/10.3390/pathogens8030093 - 28 Jun 2019
Cited by 36 | Viewed by 4872
Abstract
Bacterial biofilm on medical devices is difficult to eradicate. Many have capitalized the anti-infective capability of silver ions (Ag+) by incorporating nano-silver (nAg) in a biodegradable coating, which is then laid on polymeric medical devices. However, such coating can be subjected [...] Read more.
Bacterial biofilm on medical devices is difficult to eradicate. Many have capitalized the anti-infective capability of silver ions (Ag+) by incorporating nano-silver (nAg) in a biodegradable coating, which is then laid on polymeric medical devices. However, such coating can be subjected to premature dissolution, particularly in harsh diseased tissue microenvironment, leading to rapid nAg clearance. It stands to reason that impregnating nAg directly onto the device, at the surface, is a more ideal solution. We tested this concept for a corneal prosthesis by immobilizing nAg and nano-hydroxyapatite (nHAp) on poly(methyl methacrylate), and tested its biocompatibility with human stromal cells and antimicrobial performance against biofilm-forming pathogens, Pseudomonas aeruginosa and Staphylococcus aureus. Three different dual-functionalized substrates—high Ag (referred to as 75:25 HAp:Ag); intermediate Ag (95:5 HAp:Ag); and low Ag (99:1 HAp:Ag) were studied. The 75:25 HAp:Ag was effective in inhibiting biofilm formation, but was cytotoxic. The 95:5 HAp:Ag showed the best selectivity among the three substrates; it prevented biofilm formation of both pathogens and had excellent biocompatibility. The coating was also effective in eliminating non-adherent bacteria in the culture media. However, a 28-day incubation in artificial tear fluid revealed a ~40% reduction in Ag+ release, compared to freshly-coated substrates. The reduction affected the inhibition of S. aureus growth, but not the P. aeruginosa. Our findings suggest that Ag+ released from surface-immobilized nAg diminishes over time and becomes less effective in suppressing biofilm formation of Gram-positive bacteria, such as S. aureus. This advocates the coating, more as a protection against perioperative and early postoperative infections, and less as a long-term preventive solution. Full article
(This article belongs to the Section Vaccines and Therapeutic Developments)
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22 pages, 5529 KB  
Article
Host-Pathogen Interactions of Mycoplasma mycoides in Caprine and Bovine Precision-Cut Lung Slices (PCLS) Models
by Yenehiwot Berhanu Weldearegay, Sandy Müller, Jana Hänske, Anja Schulze, Aline Kostka, Nancy Rüger, Marion Hewicker-Trautwein, Ralph Brehm, Peter Valentin-Weigand, Robert Kammerer, Joerg Jores and Jochen Meens
Pathogens 2019, 8(2), 82; https://doi.org/10.3390/pathogens8020082 - 20 Jun 2019
Cited by 19 | Viewed by 6486
Abstract
Respiratory infections caused by mycoplasma species in ruminants lead to considerable economic losses. Two important ruminant pathogens are Mycoplasma mycoides subsp. Mycoides (Mmm), the aetiological agent of contagious bovine pleuropneumonia and Mycoplasma mycoides subsp. capri (Mmc), which causes pneumonia, [...] Read more.
Respiratory infections caused by mycoplasma species in ruminants lead to considerable economic losses. Two important ruminant pathogens are Mycoplasma mycoides subsp. Mycoides (Mmm), the aetiological agent of contagious bovine pleuropneumonia and Mycoplasma mycoides subsp. capri (Mmc), which causes pneumonia, mastitis, arthritis, keratitis, and septicemia in goats. We established precision cut lung slices (PCLS) infection model for Mmm and Mmc to study host-pathogen interactions. We monitored infection over time using immunohistological analysis and electron microscopy. Moreover, infection burden was monitored by plating and quantitative real-time PCR. Results were compared with lungs from experimentally infected goats and cattle. Lungs from healthy goats and cattle were also included as controls. PCLS remained viable for up to two weeks. Both subspecies adhered to ciliated cells. However, the titer of Mmm in caprine PCLS decreased over time, indicating species specificity of Mmm. Mmc showed higher tropism to sub-bronchiolar tissue in caprine PCLS, which increased in a time-dependent manner. Moreover, Mmc was abundantly observed on pulmonary endothelial cells, indicating partially, how it causes systemic disease. Tissue destruction upon prolonged infection of slices was comparable to the in vivo samples. Therefore, PCLS represents a novel ex vivo model to study host-pathogen interaction in livestock mycoplasma. Full article
(This article belongs to the Section Animal Pathogens)
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18 pages, 1840 KB  
Article
Evolutionary Dynamics in the RNA Bacteriophage Qβ Depends on the Pattern of Change in Selective Pressures
by Pilar Somovilla, Susanna Manrubia and Ester Lázaro
Pathogens 2019, 8(2), 80; https://doi.org/10.3390/pathogens8020080 - 18 Jun 2019
Cited by 10 | Viewed by 4733
Abstract
The rate of change in selective pressures is one of the main factors that determines the likelihood that populations can adapt to stress conditions. Generally, the reduction in the population size that accompanies abrupt environmental changes makes it difficult to generate and select [...] Read more.
The rate of change in selective pressures is one of the main factors that determines the likelihood that populations can adapt to stress conditions. Generally, the reduction in the population size that accompanies abrupt environmental changes makes it difficult to generate and select adaptive mutations. However, in systems with high genetic diversity, as happens in RNA viruses, mutations with beneficial effects under new conditions can already be present in the population, facilitating adaptation. In this work, we have propagated an RNA bacteriophage (Qβ) at temperatures higher than the optimum, following different patterns of change. We have determined the fitness values and the consensus sequences of all lineages throughout the evolutionary process in order to establish correspondences between fitness variations and adaptive pathways. Our results show that populations subjected to a sudden temperature change gain fitness and fix mutations faster than those subjected to gradual changes, differing also in the particular selected mutations. The life-history of populations prior to the environmental change has great importance in the dynamics of adaptation. The conclusion is that in the bacteriophage Qβ, the standing genetic diversity together with the rate of temperature change determine both the rapidity of adaptation and the followed evolutionary pathways. Full article
(This article belongs to the Special Issue Modeling Virus Dynamics and Evolution)
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25 pages, 922 KB  
Review
Biocontrol of Cereal Crop Diseases Using Streptomycetes
by Jake T. Newitt, Samuel M. M. Prudence, Matthew I. Hutchings and Sarah F. Worsley
Pathogens 2019, 8(2), 78; https://doi.org/10.3390/pathogens8020078 - 13 Jun 2019
Cited by 110 | Viewed by 14757
Abstract
A growing world population and an increasing demand for greater food production requires that crop losses caused by pests and diseases are dramatically reduced. Concurrently, sustainability targets mean that alternatives to chemical pesticides are becoming increasingly desirable. Bacteria in the plant root microbiome [...] Read more.
A growing world population and an increasing demand for greater food production requires that crop losses caused by pests and diseases are dramatically reduced. Concurrently, sustainability targets mean that alternatives to chemical pesticides are becoming increasingly desirable. Bacteria in the plant root microbiome can protect their plant host against pests and pathogenic infection. In particular, Streptomyces species are well-known to produce a range of secondary metabolites that can inhibit the growth of phytopathogens. Streptomyces are abundant in soils and are also enriched in the root microbiomes of many different plant species, including those grown as economically and nutritionally valuable cereal crops. In this review we discuss the potential of Streptomyces to protect against some of the most damaging cereal crop diseases, particularly those caused by fungal pathogens. We also explore factors that may improve the efficacy of these strains as biocontrol agents in situ, as well as the possibility of exploiting plant mechanisms, such as root exudation, that enable the recruitment of microbial species from the soil to the root microbiome. We argue that a greater understanding of these mechanisms may enable the development of protective plant root microbiomes with a greater abundance of beneficial bacteria, such as Streptomyces species. Full article
(This article belongs to the Special Issue Streptomyces Microbiomes in Agriculture)
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15 pages, 1425 KB  
Review
Variable and Variant Protein Multigene Families in Babesia bovis Persistence
by David R. Allred
Pathogens 2019, 8(2), 76; https://doi.org/10.3390/pathogens8020076 - 11 Jun 2019
Cited by 19 | Viewed by 4833
Abstract
Cattle infected with Babesia bovis face a bifurcated fate: Either die of the severe acute infection, or survive and carry for many years a highly persistent but generally asymptomatic infection. In this review, the author describes known and potential contributions of three variable [...] Read more.
Cattle infected with Babesia bovis face a bifurcated fate: Either die of the severe acute infection, or survive and carry for many years a highly persistent but generally asymptomatic infection. In this review, the author describes known and potential contributions of three variable or highly variant multigene-encoded families of proteins to persistence in the bovine host, and the mechanisms by which variability arises among these families. Ramifications arising from this variability are discussed. Full article
(This article belongs to the Special Issue Persistence in Babesia)
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15 pages, 815 KB  
Review
A Contemporary View of Respiratory Syncytial Virus (RSV) Biology and Strain-Specific Differences
by Mansi C. Pandya, Sean M. Callahan, Kyryll G. Savchenko and Christopher C. Stobart
Pathogens 2019, 8(2), 67; https://doi.org/10.3390/pathogens8020067 - 21 May 2019
Cited by 57 | Viewed by 9920
Abstract
Respiratory syncytial virus (RSV) is a human respiratory pathogen which remains a leading viral cause of hospitalizations and mortality among infants in their first year of life. Here, we review the biology of RSV, the primary laboratory isolates or strains which have been [...] Read more.
Respiratory syncytial virus (RSV) is a human respiratory pathogen which remains a leading viral cause of hospitalizations and mortality among infants in their first year of life. Here, we review the biology of RSV, the primary laboratory isolates or strains which have been used to best characterize the virus since its discovery in 1956, and discuss the implications for genetic and functional variations between the established laboratory strains and the recently identified clinical isolates. Full article
(This article belongs to the Special Issue Virus-Host Interactions of Respiratory Syncytial Virus (RSV))
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41 pages, 2199 KB  
Review
Fungal-Bacterial Interactions in Health and Disease
by Wibke Krüger, Sarah Vielreicher, Mario Kapitan, Ilse D. Jacobsen and Maria Joanna Niemiec
Pathogens 2019, 8(2), 70; https://doi.org/10.3390/pathogens8020070 - 21 May 2019
Cited by 169 | Viewed by 21433
Abstract
Fungi and bacteria encounter each other in various niches of the human body. There, they interact directly with one another or indirectly via the host response. In both cases, interactions can affect host health and disease. In the present review, we summarized current [...] Read more.
Fungi and bacteria encounter each other in various niches of the human body. There, they interact directly with one another or indirectly via the host response. In both cases, interactions can affect host health and disease. In the present review, we summarized current knowledge on fungal-bacterial interactions during their commensal and pathogenic lifestyle. We focus on distinct mucosal niches: the oral cavity, lung, gut, and vagina. In addition, we describe interactions during bloodstream and wound infections and the possible consequences for the human host. Full article
(This article belongs to the Special Issue Immunology of Fungal Infections)
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13 pages, 1404 KB  
Article
Putative Periodontal Pathogens, Filifactor alocis and Peptoanaerobacter stomatis, Induce Differential Cytokine and Chemokine Production by Human Neutrophils
by Aruna Vashishta, Emeri Jimenez-Flores, Christopher K. Klaes, Shifu Tian, Irina Miralda, Richard J. Lamont and Silvia M. Uriarte
Pathogens 2019, 8(2), 59; https://doi.org/10.3390/pathogens8020059 - 1 May 2019
Cited by 28 | Viewed by 5037
Abstract
Periodontitis is a highly prevalent infectious disease that affects ~ 50% of the adults in the USA alone. Two Gram-positive anaerobic oral bacteria, Filifactor alocis and Peptoanaerobacter stomatis, have emerged as important periodontal pathogens. Neutrophils are a major component of the innate [...] Read more.
Periodontitis is a highly prevalent infectious disease that affects ~ 50% of the adults in the USA alone. Two Gram-positive anaerobic oral bacteria, Filifactor alocis and Peptoanaerobacter stomatis, have emerged as important periodontal pathogens. Neutrophils are a major component of the innate host response in the gingival tissue, and the contribution of neutrophil-derived cytokines and chemokines plays a central role in disease progression. The pattern of cytokines and chemokines released by human neutrophils upon stimulation with newly appreciated periodontal bacteria compared to the keystone oral pathogen Porphyromonas gingivalis was investigated. Our results showed that both F. alocis and P. stomatis triggered TLR2/6 activation. F. alocis induced significant changes in gene expression of cytokines and chemokines in human neutrophils compared to unstimulated cells. However, except for IL-1ra, neutrophils released lower levels of cytokines and chemokines in response to F. alocis compared to P. stomatis. Furthermore, bacteria-free conditioned supernatant collected from neutrophils challenged with P. stomatis, but not from P. gingivalis or F. alocis, was chemotactic towards both neutrophils and monocytes. Elucidating stimuli-specific modulation of human neutrophil effector functions in the context of dysbiotic microbial community constituents provides valuable information for understanding the pathogenesis of periodontal diseases. Full article
(This article belongs to the Section Immunological Responses and Immune Defense Mechanisms)
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13 pages, 4201 KB  
Article
Inhibition of Pseudomonas aeruginosa Biofilm Formation with Surface Modified Polymeric Nanoparticles
by Tyler R. Flockton, Logan Schnorbus, Agustin Araujo, Jill Adams, Maryjane Hammel and Lark J. Perez
Pathogens 2019, 8(2), 55; https://doi.org/10.3390/pathogens8020055 - 24 Apr 2019
Cited by 36 | Viewed by 7282
Abstract
The gram-negative bacterial pathogen Pseudomonas aeruginosa represents a prominent clinical concern. Due to the observed high levels of antibiotic resistance, copious biofilm formation, and wide array of virulence factors produced by these bacteria, new treatment technologies are required. Here, we present the development [...] Read more.
The gram-negative bacterial pathogen Pseudomonas aeruginosa represents a prominent clinical concern. Due to the observed high levels of antibiotic resistance, copious biofilm formation, and wide array of virulence factors produced by these bacteria, new treatment technologies are required. Here, we present the development of a series of P. aeruginosa LecA-targeted polymeric nanoparticles and demonstrate the anti-adhesion and biofilm inhibitory properties of these constructs. Full article
(This article belongs to the Special Issue Signaling Systems in Pseudomonas aeruginosa Biofilm)
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23 pages, 1440 KB  
Review
Candida albicans Interactions with Mucosal Surfaces during Health and Disease
by Spyridoula-Angeliki Nikou, Nessim Kichik, Rhys Brown, Nicole O. Ponde, Jemima Ho, Julian R. Naglik and Jonathan P. Richardson
Pathogens 2019, 8(2), 53; https://doi.org/10.3390/pathogens8020053 - 22 Apr 2019
Cited by 73 | Viewed by 20948
Abstract
Flexible adaptation to the host environment is a critical trait that underpins the success of numerous microbes. The polymorphic fungus Candida albicans has evolved to persist in the numerous challenging niches of the human body. The interaction of C. albicans with a mucosal [...] Read more.
Flexible adaptation to the host environment is a critical trait that underpins the success of numerous microbes. The polymorphic fungus Candida albicans has evolved to persist in the numerous challenging niches of the human body. The interaction of C. albicans with a mucosal surface is an essential prerequisite for fungal colonisation and epitomises the complex interface between microbe and host. C. albicans exhibits numerous adaptations to a healthy host that permit commensal colonisation of mucosal surfaces without provoking an overt immune response that may lead to clearance. Conversely, fungal adaptation to impaired immune fitness at mucosal surfaces enables pathogenic infiltration into underlying tissues, often with devastating consequences. This review will summarise our current understanding of the complex interactions that occur between C. albicans and the mucosal surfaces of the human body. Full article
(This article belongs to the Special Issue Immunology of Fungal Infections)
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11 pages, 256 KB  
Review
Interleukin-17 in Antifungal Immunity
by Florian Sparber and Salomé LeibundGut-Landmann
Pathogens 2019, 8(2), 54; https://doi.org/10.3390/pathogens8020054 - 22 Apr 2019
Cited by 72 | Viewed by 6361
Abstract
The field of IL-17 biology has received much attention over the last decade owing to the pathogenic role of this cytokine in psoriasis and other autoinflammatory disorders and the successful implementation of IL-17-targeting therapies in patients suffering from these diseases. IL-17-mediated pathologies are [...] Read more.
The field of IL-17 biology has received much attention over the last decade owing to the pathogenic role of this cytokine in psoriasis and other autoinflammatory disorders and the successful implementation of IL-17-targeting therapies in patients suffering from these diseases. IL-17-mediated pathologies are contrasted by the important host beneficial effects of this cytokine. IL-17 is essential for regulating microbial colonization in barrier tissues. Rare congenital defects in the IL-17 pathway exemplify the relevance of IL-17 in protective immunity against the opportunistic fungal pathogen C. albicans. However, more recently, evidence is accumulating that IL-17 can also provide protection against fungi other than C. albicans. Importantly, protective IL-17 responses directed against commensal fungi can, under certain conditions, promote inflammation with detrimental consequences for the host, thereby assigning fungi a new role as disease-promoting factors apart from their role as potential infectious agents. Full article
(This article belongs to the Special Issue Immunology of Fungal Infections)
24 pages, 1002 KB  
Review
ApiAP2 Transcription Factors in Apicomplexan Parasites
by Myriam D. Jeninga, Jennifer E. Quinn and Michaela Petter
Pathogens 2019, 8(2), 47; https://doi.org/10.3390/pathogens8020047 - 7 Apr 2019
Cited by 86 | Viewed by 11559
Abstract
Apicomplexan parasites are protozoan organisms that are characterised by complex life cycles and they include medically important species, such as the malaria parasite Plasmodium and the causative agents of toxoplasmosis (Toxoplasma gondii) and cryptosporidiosis (Cryptosporidium spp.). Apicomplexan parasites can infect [...] Read more.
Apicomplexan parasites are protozoan organisms that are characterised by complex life cycles and they include medically important species, such as the malaria parasite Plasmodium and the causative agents of toxoplasmosis (Toxoplasma gondii) and cryptosporidiosis (Cryptosporidium spp.). Apicomplexan parasites can infect one or more hosts, in which they differentiate into several morphologically and metabolically distinct life cycle stages. These developmental transitions rely on changes in gene expression. In the last few years, the important roles of different members of the ApiAP2 transcription factor family in regulating life cycle transitions and other aspects of parasite biology have become apparent. Here, we review recent progress in our understanding of the different members of the ApiAP2 transcription factor family in apicomplexan parasites. Full article
(This article belongs to the Section Human Pathogens)
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