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Microorganisms
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Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment
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Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Medical Microbiology".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 26630

Special Issue Editors

Prof. Dr. Max Maurin

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Guest Editor
1. Centre National de Référence des Francisella, Institut de Biologie etde Pathologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
2. Centre National de la Recherche Scientifique, TIMC, Université Grenoble Alpes, Grenoble, France
Interests: zoonoses; tularemia; brucellosis; bartonellosis; diagnosis; antibiotic susceptibility testing; antibiotic resistance
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Marina Santic

E-Mail Website
Guest Editor
Faculty of Medicine, University of Rijeka, Rijeka, Croatia
Interests: Francisella; Legionella; pathogenesis; microbe-host interaction

Special Issue Information

Dear Colleagues,

Tularemia is a zoonosis caused by Francisella tularensis, a Gram-negative, facultative intracellular bacterium. Renewed medical and scientific interest for this pathogen has arisen since the 2000s, owing to its classification by the Center for Diseases Control and Prevention (USA) among the list of biological threat agents. Since then, outstanding research has been done, leading to significant discoveries in different fields, including taxonomy, phylogeny, phylogeography, epidemiology, and virulence mechanisms of F. tularensis, as well as the pathogenesis of tularemia. The most significant findings have arisen from genomic studies after hundreds of F. tularensis genomes were made available to the scientific community. The development of innovative genetic techniques has also made it possible to deepen knowledge in the field of virulence of Francisella tularensis. From a medical point of view, the extension of the tularemia endemic zone (especially in the southern hemisphere) and the description of new clinical manifestations of the disease are the most striking facts. Tularemia diagnostic methods have been diversified, improved, and better evaluated for their reliability in real clinical situations. Although therapeutic recommendations concerning tularemia are available, therapeutic failures and relapses remain frequent, demonstrating that the optimum treatment for the various forms of the disease remains to be defined.

The purpose of this topic is to provide an overall update on the medical and scientific knowledge concerning tularemia pathogenesis, diagnostic, prevention, and treatment. Current advances on the following aspects will be taken into account: clinical aspects, clinical microbiology, clinical pathology, histopathology, cell biology, systems biology, genetics, genomics, and metabolomics. The Guest-Editors of this Research Topic welcome original research articles and reviews on F. tularensis and tularemia that may include (but not limited to) the following aspects:

  • tularemia pathogenesis, including cell and animal models, clinical pathology, and genetics
  • tularemia diagnosis, prognosis, prevention, and treatment

Prof. Dr. Max Maurin
Prof. Dr. Marina Santic
Guest Editors

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Published Papers (8 papers)

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Research

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16 pages, 3037 KiB  
Article
Virulence of Francisella tularensis Subspecies holarctica Biovar japonica and Phenotypic Change during Serial Passages on Artificial Media
by Akitoyo Hotta, Neekun Sharma, Osamu Fujita, Akihiko Uda, Kiyoshi Tanabayashi, Deyu Tian, Akio Yamada, Shigeru Morikawa and Ken Maeda
Microorganisms 2020, 8(12), 1881; https://doi.org/10.3390/microorganisms8121881 - 27 Nov 2020
Cited by 1 | Viewed by 2362
Abstract
Francisella tularensis (F. tularensis) is the etiological agent of the zoonotic disease tularemia. F. tularensis subspecies holarctica biovar japonica has rarely been isolated in Japan and is considered to have moderate virulence, although the biological properties of fresh isolates have not [...] Read more.
Francisella tularensis (F. tularensis) is the etiological agent of the zoonotic disease tularemia. F. tularensis subspecies holarctica biovar japonica has rarely been isolated in Japan and is considered to have moderate virulence, although the biological properties of fresh isolates have not been analyzed in detail. Here, we analyzed the virulence of two strains of F. tularensis subspecies holarctica biovar japonica (NVF1 and KU-1) and their phenotypic stability during serial passages in Eugon chocolate agar (ECA) and Chamberlain’s chemically defined medium (CDM) based agar (CDMA). C57BL/6 mice intradermally inoculated with 101 colony-forming units of NVF1 or KU-1 died within 9 days, with a median time to death of 7.5 and 7 days, respectively. Both NVF1 and KU-1 strains passaged on ECA 10 times had comparable virulence prior to passaging, whereas strains passaged on ECA 20 times and on CDMA 50 times were attenuated. Attenuated strains had decreased viability in 0.01% H2O2 and lower intracellular growth rates, suggesting both properties are important for F. tularensis virulence. Additionally, passage on ECA of the KU-1 strains altered lipopolysaccharide antigenicity and bacterial susceptibility to β-lactam antibiotics. Our data demonstrate F. tularensis strain virulence in Japan and contribute to understanding phenotypic differences between natural and laboratory environments. Full article
(This article belongs to the Special Issue Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment)
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14 pages, 1574 KiB  
Article
Outbreak of Tularemia in a Group of Hunters in Germany in 2018—Kinetics of Antibody and Cytokine Responses
by Daniela Jacob, Anne Barduhn, Dennis Tappe, Jessica Rauch, Klaus Heuner, Daniela Hierhammer, Katharina vom Berge, Julia M. Riehm, Matthias Hanczaruk, Stefanie Böhm, Merle M. Böhmer, Regina Konrad, Berit Bouschery, Marc Dauer, Elisabeth Schichtl, Hamid Hossain and Roland Grunow
Microorganisms 2020, 8(11), 1645; https://doi.org/10.3390/microorganisms8111645 - 23 Oct 2020
Cited by 6 | Viewed by 2383
Abstract
In November 2018, an outbreak of tularemia occurred among hare hunters in Bavaria, Germany. At least one infected hare was confirmed as the source of infection. A number of hunting dogs showed elevated antibody titers to Francisella tularensis, but the absence of [...] Read more.
In November 2018, an outbreak of tularemia occurred among hare hunters in Bavaria, Germany. At least one infected hare was confirmed as the source of infection. A number of hunting dogs showed elevated antibody titers to Francisella tularensis, but the absence of titer increases in subsequent samples did not point to acute infections in dogs. Altogether, 12 persons associated with this hare hunt could be diagnosed with acute tularemia by detection of specific antibodies. In nine patients, the antibody and cytokine responses could be monitored over time. Eight out of these nine patients had developed detectable antibodies three weeks after exposure; in one individual the antibody response was delayed. All patients showed an increase in various cytokines and chemokines with a peak for most mediators in the first week after exposure. Cytokine levels showed individual variations, with high and low responders. The kinetics of seroconversion has implications on serological diagnoses of tularemia. Full article
(This article belongs to the Special Issue Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment)
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13 pages, 3616 KiB  
Article
Atg5-Deficient Mice Infected with Francisella tularensis LVS Demonstrate Increased Survival and Less Severe Pathology in Internal Organs
by Ina Kelava, Mirna Mihelčić, Mateja Ožanič, Valentina Marečić, Maša Knežević, Marija Ćurlin, Sanja Štifter, Anders Sjöstedt and Marina Šantić
Microorganisms 2020, 8(10), 1531; https://doi.org/10.3390/microorganisms8101531 - 6 Oct 2020
Cited by 4 | Viewed by 2357
Abstract
Francisella tularensis is a highly virulent intracellular pathogen that proliferates within various cell types and can infect a multitude of animal species. Francisella escapes the phagosome rapidly after infection and reaches the host cell cytosol where bacteria undergo extensive replication. Once cytosolic, Francisella [...] Read more.
Francisella tularensis is a highly virulent intracellular pathogen that proliferates within various cell types and can infect a multitude of animal species. Francisella escapes the phagosome rapidly after infection and reaches the host cell cytosol where bacteria undergo extensive replication. Once cytosolic, Francisella becomes a target of an autophagy-mediated process. The mechanisms by which autophagy plays a role in replication of this cytosolic pathogen have not been fully elucidated. In vitro, F. tularensis avoids degradation via autophagy and the autophagy process provides nutrients that support its intracellular replication, but the role of autophagy in vivo is unknown. Here, we investigated the role of autophagy in the pathogenesis of tularemia by using transgenic mice deficient in Atg5 in the myeloid lineage. The infection of Atg5-deficient mice with Francisella tularensis subsp. holarctica live vaccine strain (LVS) resulted in increased survival, significantly reduced bacterial burden in the mouse organs, and less severe histopathological changes in the spleen, liver and lung tissues. The data highlight the contribution of Atg5 in the pathogenesis of tularemia in vivo. Full article
(This article belongs to the Special Issue Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment)
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12 pages, 7392 KiB  
Article
Increased Sensitivity of Amoeba-Grown Francisella Species to Disinfectants
by Maša Knežević, Valentina Marečić, Mateja Ožanič, Nikolina Špoljarić, Ina Kelava, Marija Ćurlin, Yousef Abu Kwaik, Mirna Mihelčić and Marina Šantić
Microorganisms 2020, 8(9), 1260; https://doi.org/10.3390/microorganisms8091260 - 20 Aug 2020
Cited by 4 | Viewed by 2616
Abstract
Francisella tularensis is a highly infectious, intracellular bacterium and it is the causative agent of tularemia. The bacterium has been isolated from more than 250 species, including protozoa. Previous studies have shown that the growth of Legionella pneumophila within the amoeba results in [...] Read more.
Francisella tularensis is a highly infectious, intracellular bacterium and it is the causative agent of tularemia. The bacterium has been isolated from more than 250 species, including protozoa. Previous studies have shown that the growth of Legionella pneumophila within the amoeba results in a dramatic increase in the resistance to disinfectants. Since Francisella persists in the environment for years, this study investigates whether Acanthamoeba castellanii-grown F. novicida exhibits an alteration in the resistance to disinfectants. The disinfectants used are didecyldimethylammonium chloride (DDAC) combined with isopropyl alcohol (D1), benzalkonium chloride combined with DDAC and formic acid (D2), and polyhexamethylene biguanide (PHMB, D3). The effect of disinfectants on the bacterial viability is determined by a colony-forming unit (CFU), by transmission electron microscopy (TEM), by fluorescence microscopy, and the damage of the bacterial membrane. Our data has shown that only a one-log10 loss in bacterial viability is exhibited upon treatment of agar-grown Francisella, while in amoeba-grown Francisella there was a three-log10 difference with D3. The D1 disinfectant sterilized the bacteria within 10 s. The treatment of agar-grown F. novicida with D2 reduces bacterial viability by seven-log10 within 10 s and 15 min, respectively. Surprisingly, the treatment of amoeba-grown F. novicida with D2 results in a total loss of bacterial viability. In conclusion, A. castellanii-grown F. novicida is more susceptible to many disinfectants. Full article
(This article belongs to the Special Issue Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment)
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15 pages, 1308 KiB  
Article
Optimized MALDI TOF Mass Spectrometry Identification of Francisella tularensis Subsp. holarctica
by Sofiane Regoui, Aurélie Hennebique, Thomas Girard, Sandrine Boisset, Yvan Caspar and Max Maurin
Microorganisms 2020, 8(8), 1143; https://doi.org/10.3390/microorganisms8081143 - 28 Jul 2020
Cited by 11 | Viewed by 2727
Abstract
Francisella tularensis is a tier 1 agent causing the zoonosis tularemia. This highly infectious Gram-negative bacterium is occasionally isolated from human samples (especially blood samples) in routine clinical microbiology laboratories. A rapid and accurate method for identifying this pathogen is needed in order [...] Read more.
Francisella tularensis is a tier 1 agent causing the zoonosis tularemia. This highly infectious Gram-negative bacterium is occasionally isolated from human samples (especially blood samples) in routine clinical microbiology laboratories. A rapid and accurate method for identifying this pathogen is needed in order to optimize the infected patient’s healthcare management and prevent contamination of the laboratory personnel. MALDI TOF mass spectrometry has become the gold standard for the rapid identification of most human pathogens. However, F. tularensis identification using such technology and commercially available databases is currently considered unreliable. Real-time PCR-based methods for rapid detection and accurate identification of F. tularensis are not available in many laboratories. As a national reference center for tularemia, we developed a MALDI TOF database allowing accurate identification of the species F. tularensis and its differentiation from the closely related neighbor species F. tularensis subsp. novicida and F. philomiragia. The sensitivity and specificity of this database were validated by testing 71 F. tularensis strains and 165 strains from 63 species not belonging to the Francisella genus. We obtained accurate identification at the species level and differentiation of all the tested bacterial strains. In particular, F. tularensis could be accurately differentiated from other small Gram-negative bacilli occasionally isolated from human samples, including species of the HACEK group and Brucella melitensis. Full article
(This article belongs to the Special Issue Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment)
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Review

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15 pages, 887 KiB  
Review
Differential Immune Response Following Intranasal and Intradermal Infection with Francisella tularensis: Implications for Vaccine Development
by McKayla J. Nicol, David R. Williamson, David E. Place and Girish S. Kirimanjeswara
Microorganisms 2021, 9(5), 973; https://doi.org/10.3390/microorganisms9050973 - 30 Apr 2021
Cited by 5 | Viewed by 5195
Abstract
Francisella tularensis (Ft) is a Gram-negative, facultative intracellular coccobacillus that is the etiological agent of tularemia. Interestingly, the disease tularemia has variable clinical presentations that are dependent upon the route of infection with Ft. Two of the most likely routes of [...] Read more.
Francisella tularensis (Ft) is a Gram-negative, facultative intracellular coccobacillus that is the etiological agent of tularemia. Interestingly, the disease tularemia has variable clinical presentations that are dependent upon the route of infection with Ft. Two of the most likely routes of Ft infection include intranasal and intradermal, which result in pneumonic and ulceroglandular tularemia, respectively. While there are several differences between these two forms of tularemia, the most notable disparity is between mortality rates: the mortality rate following pneumonic tularemia is over ten times that of the ulceroglandular disease. Understanding the differences between intradermal and intranasal Ft infections is important not only for clinical diagnoses and treatment but also for the development of a safe and effective vaccine. However, the immune correlates of protection against Ft, especially within the context of infection by disparate routes, are not yet fully understood. Recent advances in different animal models have revealed new insights in the complex interplay of innate and adaptive immune responses, indicating dissimilar patterns in both responses following infection with Ft via different routes. Further investigation of these differences will be crucial to predicting disease outcomes and inducing protective immunity via vaccination or natural infection. Full article
(This article belongs to the Special Issue Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment)
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14 pages, 888 KiB  
Review
Tularemia as a Mosquito-Borne Disease
by Zakaria Abdellahoum, Max Maurin and Idir Bitam
Microorganisms 2021, 9(1), 26; https://doi.org/10.3390/microorganisms9010026 - 23 Dec 2020
Cited by 20 | Viewed by 4170
Abstract
Francisella tularensis (Ft) is the etiological agent of tularemia, a disease known for over 100 years in the northern hemisphere. Ft includes four subspecies, of which two are the etiologic agents of tularemia: Ft subsp. tularensis (Ftt) and Ft subsp. holarctica (Fth), mainly [...] Read more.
Francisella tularensis (Ft) is the etiological agent of tularemia, a disease known for over 100 years in the northern hemisphere. Ft includes four subspecies, of which two are the etiologic agents of tularemia: Ft subsp. tularensis (Ftt) and Ft subsp. holarctica (Fth), mainly distributed in North America and the whole northern hemisphere, respectively. Several routes of human infection with these bacteria exist, notably through bites of Ixodidae ticks. However, mosquitoes represent the main vectors of Fth in Scandinavia, where large tularemia outbreaks have occurred, usually during the warm season. The mechanisms making mosquitoes vectors of Fth are still unclear. This review covers the inventory of research work and epidemiological data linking tularemia to mosquitoes in Scandinavia and highlights the gaps in understanding mosquitoes and Ft interactions. Full article
(This article belongs to the Special Issue Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment)
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16 pages, 285 KiB  
Review
Control of Francisella tularensis Virulence at Gene Level: Network of Transcription Factors
by Petra Spidlova, Pavla Stojkova, Anders Sjöstedt and Jiri Stulik
Microorganisms 2020, 8(10), 1622; https://doi.org/10.3390/microorganisms8101622 - 21 Oct 2020
Cited by 12 | Viewed by 3333
Abstract
Regulation of gene transcription is the initial step in the complex process that controls gene expression within bacteria. Transcriptional control involves the joint effort of RNA polymerases and numerous other regulatory factors. Whether global or local, positive or negative, regulators play an essential [...] Read more.
Regulation of gene transcription is the initial step in the complex process that controls gene expression within bacteria. Transcriptional control involves the joint effort of RNA polymerases and numerous other regulatory factors. Whether global or local, positive or negative, regulators play an essential role in the bacterial cell. For instance, some regulators specifically modify the transcription of virulence genes, thereby being indispensable to pathogenic bacteria. Here, we provide a comprehensive overview of important transcription factors and DNA-binding proteins described for the virulent bacterium Francisella tularensis, the causative agent of tularemia. This is an unexplored research area, and the poorly described networks of transcription factors merit additional experimental studies to help elucidate the molecular mechanisms of pathogenesis in this bacterium, and how they contribute to disease. Full article
(This article belongs to the Special Issue Tularemia: Pathogenesis, Diagnostic, Prevention, and Treatment)
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