Special Issue "Medical Advances in Viral Hemorrhagic Fever Research"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 July 2019).

Special Issue Editors

Dr. Ian Crozier

Guest Editor
NIH/NIAID Integrated Research Facility at Fort Detrick (IRF-Frederick), supported by Clinical Monitoring Research Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
Interests: emerging infectious diseases; viral hemorrhagic fevers; mechanisms of immune privilege and viral persistence; filoviruses; arenaviruses
Dr. Jens H. Kuhn
Website
Guest Editor
NIH/NIAID Integrated Research Facility at Fort Detrick (IRF-Frederick), B-8200 Research Plaza, Fort Detrick, Frederick, MD 21702, USA
Interests: arenaviruses; biodefense; bioengagement; BSL-4; filoviruses; henipaviruses; Kyasanur Forest disease virus; nairoviruses; phleboviruses; Omsk hemorrhagic fever virus; simian hemorrhagic fever virus
Special Issues and Collections in MDPI journals
Dr. Sheli R. Radoshitzky
Website
Guest Editor
United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Fort Detrick, Frederick, MD 21702, USA
Interests: molecular virology; emerging infectious diseases; viral hemorrhagic fevers; arenaviruses; filoviruses; alphaviruses

Special Issue Information

Dear Colleagues,

Recent large outbreaks of Ebola and Marburg virus disease (Eastern and Western Africa), Lassa fever (Western Africa), Crimean Congo hemorrhagic fever (Africa, Eastern Europe, Western Asia) and severe fever with thrombocytopenia syndrome (China, Japan, South Korea) have afforded higher-resolution views at human clinical diseases historically referred to as “viral hemorrhagic Fevers.” In addition to updating our understanding of the spectrum and severity of acute disease syndromes, recent encounters have renewed interest in, e.g., the role of pathogen–agnostic care in addition to virus-specific countermeasures, clinical sequelae after infection, and viral persistence potentially associated with inflammatory syndromes or risk of transmission and outbreak re-ignition. Although there are no FDA-approved medical countermeasures against these viral agents, increased funding, interest, and novel technologies have accelerated research and understanding of many medical aspects of these and other, more neglected (e.g., Alkhurma, Chapare, Guanarito, Kyasanur Forest disease, Lujo, Omsk hemorrhagic fever, Sabiá viruses), viral hemorrhagic fever-causing pathogens. New clinical data and at-bedside approached, advanced genomics and proteomics tools, CRISPR-Cas9 screens, and novel off-label or IND-level vaccine and therapeutics platforms have all contributed (or have the potential) to expand our knowledge of disease course, pathogenesis, and molecular epidemiology, as well as to the development of better diagnostics and medical countermeasures. The present Special Issue covers a wide range of topics focusing on human clinical disease related to such “Medical Advances in Viral Hemorrhagic Fever Research".

Dr. Ian Crozier
Dr. Jens H. Kuhn
Dr. Sheli R. Radoshitzky
Guest Editors

Manuscript Submission Information

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Keywords

  • arenaviruses
  • filoviruses
  • flaviviruses
  • bunyaviruses
  • clinical presentation
  • epidemiology/outbreak response
  • pathology/pathogenesis
  • medical countermeasures
  • diagnostics

Published Papers (17 papers)

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Research

Jump to: Review, Other

Open AccessArticle
Modeling Challenges of Ebola Virus–Host Dynamics during Infection and Treatment
Viruses 2020, 12(1), 106; https://doi.org/10.3390/v12010106 - 16 Jan 2020
Abstract
Mathematical modeling of Ebola virus (EBOV)–host dynamics during infection and treatment in vivo is in its infancy due to few studies with frequent viral kinetic data, lack of approved antiviral therapies, and limited insight into the timing of EBOV infection of cells and [...] Read more.
Mathematical modeling of Ebola virus (EBOV)–host dynamics during infection and treatment in vivo is in its infancy due to few studies with frequent viral kinetic data, lack of approved antiviral therapies, and limited insight into the timing of EBOV infection of cells and tissues throughout the body. Current in-host mathematical models simplify EBOV infection by assuming a single homogeneous compartment of infection. In particular, a recent modeling study assumed the liver as the largest solid organ targeted by EBOV infection and predicted that nearly all cells become refractory to infection within seven days of initial infection without antiviral treatment. We compared our observations of EBOV kinetics in multiple anatomic compartments and hepatocellular injury in a critically ill patient with Ebola virus disease (EVD) with this model’s predictions. We also explored the model’s predictions, with and without antiviral therapy, by recapitulating the model using published inputs and assumptions. Our findings highlight the challenges of modeling EBOV–host dynamics and therapeutic efficacy and emphasize the need for iterative interdisciplinary efforts to refine mathematical models that might advance understanding of EVD pathogenesis and treatment. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Characterization of Ebola Virus Disease (EVD) in Rhesus Monkeys for Development of EVD Therapeutics
Viruses 2020, 12(1), 92; https://doi.org/10.3390/v12010092 - 13 Jan 2020
Abstract
Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy [...] Read more.
Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy of multiple experimental EVD therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. Nonclinical studies are likely to continue to be important tools for screening and development of new candidates with improved pharmacological properties. Here, we describe a natural history study to characterize the time course and order of progression of the disease manifestations of EVD in rhesus monkeys. In 12 rhesus monkeys exposed by the intramuscular route to 1000 plaque-forming units of EBOV, multiple endpoints were monitored for 28 days following exposure. The disease progressed rapidly with mortality events occurring 7–10 days after exposure. Key disease manifestations observed consistently across the infected animals included, but were not limited to, viremia, fever, systemic inflammation, coagulopathy, lymphocytolysis, renal tubular necrosis with mineralization, and hepatocellular degeneration and necrosis. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessCommunication
Serum LPS Associated with Hantavirus and Dengue Disease Severity in Barbados
Viruses 2019, 11(9), 838; https://doi.org/10.3390/v11090838 - 09 Sep 2019
Abstract
Hantavirus and dengue virus (DENV) infections are caused by RNA viruses which infect immune systems’ cells including monocytes, macrophages and dendritic cells and occur year-round in Barbados. A retrospective serological study (2008–2015) was conducted on hantavirus and dengue patient sera confirmed by IgM [...] Read more.
Hantavirus and dengue virus (DENV) infections are caused by RNA viruses which infect immune systems’ cells including monocytes, macrophages and dendritic cells and occur year-round in Barbados. A retrospective serological study (2008–2015) was conducted on hantavirus and dengue patient sera confirmed by IgM and IgG ELISA, NS1 and RT-PCR using Limulus amoebocyte lysate (LAL) kinetic turbidimetric method to determine serum endotoxin levels. Hantavirus patients were categorized into two groups, namely (a) hospitalized and (b) non-hospitalized. Dengue patients were categorized into 3 groups using 2009 WHO dengue guidelines (a) severe dengue (SD), (b) hospitalized non-severe dengue (non-SD) and (c) non-hospitalized non-SD. Statistical analyses were conducted to determine the association of endotoxin levels with hantavirus disease severity based on hospitalization and dengue disease severity. Serum endotoxin levels are associated with hantavirus disease severity and hospitalization and dengue disease severity (p < 0.01). Similar studies have found an association of serum endotoxin levels with dengue disease severity but never with hantavirus infection. Co-detection of hantavirus- and DENV-specific IgM in some patients were observed with elevated serum endotoxin levels. In addition, previous studies observed hantavirus replication in the gut of patients, gastrointestinal tract as a possible entry route of infection and evidence of microbial translocation and its impact on hantavirus disease severity. A significant correlation of serum endotoxin and hantavirus disease severity and hospitalization in hantavirus infected patients is reported for the first time ever. In addition, serum endotoxin levels correlated with dengue disease severity. This study adds further support to the role of endotoxin in both hantavirus and dengue virus infection and disease severity and its role as a possible therapeutic target for viral haemorrhagic fevers (VHFs). Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
A Methodology for Determining Which Diseases Warrant Care in a High-Level Containment Care Unit
Viruses 2019, 11(9), 773; https://doi.org/10.3390/v11090773 - 22 Aug 2019
Abstract
Although the concept of high-level containment care (HLCC or ‘biocontainment’), dates back to 1969, the 2014–2016 outbreak of Ebola virus disease (EVD) brought with it a renewed emphasis on the use of specialized HLCC units in the care of patients with EVD. Employment [...] Read more.
Although the concept of high-level containment care (HLCC or ‘biocontainment’), dates back to 1969, the 2014–2016 outbreak of Ebola virus disease (EVD) brought with it a renewed emphasis on the use of specialized HLCC units in the care of patients with EVD. Employment of these units in the United States and Western Europe resulted in a significant decrease in mortality compared to traditional management in field settings. Moreover, this employment appeared to significantly lessen the risk of nosocomial transmission of disease; no secondary cases occurred among healthcare workers in these units. While many now accept the wisdom of utilizing HLCC units and principles in the management of EVD (and, presumably, of other transmissible and highly hazardous viral hemorrhagic fevers, such as those caused by Marburg and Lassa viruses), no consensus exists regarding additional diseases that might warrant HLCC. We propose here a construct designed to make such determinations for existing and newly discovered diseases. The construct examines infectivity (as measured by the infectious dose needed to infect 50% of a given population (ID50)), communicability (as measured by the reproductive number (R0)), and hazard (as measured by morbidity and mortality). Diseases fulfilling all three criteria (i.e., those that are highly infectious, communicable, and highly hazardous) are considered candidates for HLCC management if they also meet a fourth criterion, namely that they lack effective and available licensed countermeasures. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Characterization of Biomarker Levels in Crimean–Congo Hemorrhagic Fever and Hantavirus Fever with Renal Syndrome
Viruses 2019, 11(8), 686; https://doi.org/10.3390/v11080686 - 26 Jul 2019
Cited by 2
Abstract
Hemorrhagic fever with renal syndrome (HFRS) and Crimean-Congo hemorrhagic fever (CCHF) are important viral hemorrhagic fevers (VHF), especially in the Balkan region. Infections with Dobrava or Puumala orthohantavirus and Crimean-Congo hemorrhagic fever orthonairovirus can vary from a mild, nonspecific febrile illness, to a [...] Read more.
Hemorrhagic fever with renal syndrome (HFRS) and Crimean-Congo hemorrhagic fever (CCHF) are important viral hemorrhagic fevers (VHF), especially in the Balkan region. Infections with Dobrava or Puumala orthohantavirus and Crimean-Congo hemorrhagic fever orthonairovirus can vary from a mild, nonspecific febrile illness, to a severe disease with a fatal outcome. The pathogenesis of both diseases is poorly understood, but it has been suggested that a host’s immune mechanism might influence the pathogenesis of the diseases and survival. The aim of our study is to characterize cytokine response in patients with VHF in association with the disease progression and viral load. Forty soluble mediators of the immune response, coagulation, and endothelial dysfunction were measured in acute serum samples in 100 HFRS patients and 70 CCHF patients. HFRS and CCHF patients had significantly increased levels of IL-6, IL-12p70, IP-10, INF-γ, TNF-α, GM-CSF, MCP-3, and MIP-1b in comparison to the control group. Interestingly, HFRS patients had higher concentrations of serum MIP-1α, MIP-1β, which promote activation of macrophages and NK cells. HFRS patients had increased concentrations of IFN-γ and TNF-α, while CCHF patients had significantly higher concentrations of IFN-α and IL-8. In both, CCHF and HFRS patients’ viral load significantly correlated with IP-10. Patients with fatal outcome had significantly elevated concentrations of IL-6, IFN-α2 and MIP-1α, while GRO-α, chemokine related to activation of neutrophils and basophils, was downregulated. Our study provided a comprehensive characterization of biomarkers released in the acute stages of CCHF and HFRS. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Evaluation of Diagnostic Performance of Three Indirect Enzyme-Linked Immunosorbent Assays for the Detection of IgG Antibodies to Ebola Virus in Human Sera
Viruses 2019, 11(8), 678; https://doi.org/10.3390/v11080678 - 24 Jul 2019
Abstract
Filovirus serological diagnosis and epidemiological investigations are hampered due to the unavailability of validated immunoassays. Diagnostic performance of three indirect enzyme-linked immunosorbent assays (I-ELISA) was evaluated for the detection of IgG antibody to Ebola virus (EBOV) in human sera. One I-ELISA was based [...] Read more.
Filovirus serological diagnosis and epidemiological investigations are hampered due to the unavailability of validated immunoassays. Diagnostic performance of three indirect enzyme-linked immunosorbent assays (I-ELISA) was evaluated for the detection of IgG antibody to Ebola virus (EBOV) in human sera. One I-ELISA was based on a whole EBOV antigen (WAg) and two utilized recombinant nucleocapsid (NP) and glycoproteins (GP), respectively. Validation data sets derived from individual sera collected in South Africa (SA), representing an EBOV non-endemic country, and from sera collected during an Ebola disease (EBOD) outbreak in Sierra Leone (SL), were categorized according to the compounded results of the three I-ELISAs and real time reverse-transcription polymerase chain reaction (RT-PCR). At the cut-off values selected at 95% accuracy level by the two-graph receiver operating characteristic analysis, specificity in the SA EBOV negative serum panel (n = 273) ranged from 98.17% (GP ELISA) to 99.27% (WAg ELISA). Diagnostic specificity in the SL EBOV negative panel (n = 676) was 100% by the three ELISAs. The diagnostic sensitivity in 423 RT-PCR confirmed EBOD patients was dependent on the time when the serum was collected after onset of disease. It significantly increased 2 weeks post-onset, reaching 100% sensitivity by WAg and NP and 98.1% by GP I-ELISA. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Haemostatic Changes in Five Patients Infected with Ebola Virus
Viruses 2019, 11(7), 647; https://doi.org/10.3390/v11070647 - 15 Jul 2019
Cited by 2
Abstract
Knowledge on haemostatic changes in humans infected with Ebola virus is limited due to safety concerns and access to patient samples. Ethical approval was obtained to collect plasma samples from patients in Sierra Leone infected with Ebola virus over time and samples were [...] Read more.
Knowledge on haemostatic changes in humans infected with Ebola virus is limited due to safety concerns and access to patient samples. Ethical approval was obtained to collect plasma samples from patients in Sierra Leone infected with Ebola virus over time and samples were analysed for clotting time, fibrinogen, and D-dimer levels. Plasma from healthy volunteers was also collected by two methods to determine effect of centrifugation on test results as blood collected in Sierra Leone was not centrifuged. Collecting plasma without centrifugation only affected D-dimer values. Patients with Ebola virus disease had higher PT and APTT and D-dimer values than healthy humans with plasma collected in the same manner. Fibrinogen levels in patients with Ebola virus disease were normal or lower than values measured in healthy people. Clotting times and D-dimer levels were elevated during infection with Ebola virus but return to normal over time in patients that survived and therefore could be considered prognostic. Informative data can be obtained from plasma collected without centrifugation which could improve patient monitoring in hazardous environments. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Autophagy Promotes Infectious Particle Production of Mopeia and Lassa Viruses
Viruses 2019, 11(3), 293; https://doi.org/10.3390/v11030293 - 23 Mar 2019
Cited by 4
Abstract
Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related Old-World mammarenaviruses. LASV causes severe hemorrhagic fever with high mortality in humans, whereas no case of MOPV infection has been reported. Comparing MOPV and LASV is a powerful strategy to unravel pathogenic [...] Read more.
Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related Old-World mammarenaviruses. LASV causes severe hemorrhagic fever with high mortality in humans, whereas no case of MOPV infection has been reported. Comparing MOPV and LASV is a powerful strategy to unravel pathogenic mechanisms that occur during the course of pathogenic arenavirus infection. We used a yeast two-hybrid approach to identify cell partners of MOPV and LASV Z matrix protein in which two autophagy adaptors were identified, NDP52 and TAX1BP1. Autophagy has emerged as an important cellular defense mechanism against viral infections but its role during arenavirus infection has not been shown. Here, we demonstrate that autophagy is transiently induced by MOPV, but not LASV, in infected cells two days after infection. Impairment of the early steps of autophagy significantly decreased the production of MOPV and LASV infectious particles, whereas a blockade of the degradative steps impaired only MOPV infectious particle production. Our study provides insights into the role played by autophagy during MOPV and LASV infection and suggests that this process could partially explain their different pathogenicity. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Non-Pathogenic Mopeia Virus Induces More Robust Activation of Plasmacytoid Dendritic Cells than Lassa Virus
Viruses 2019, 11(3), 287; https://doi.org/10.3390/v11030287 - 21 Mar 2019
Cited by 1
Abstract
Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of [...] Read more.
Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of plasmacytoid dendritic cells (pDC) to LASV, as they are an important and early source of IFN-I. We compared the response of primary human pDCs to LASV and Mopeia virus (MOPV), which is very closely related to LASV, but non-pathogenic. We showed that pDCs are not productively infected by either MOPV or LASV, but produce IFN-I. However, the activation of pDCs was more robust in response to MOPV than LASV. In vivo, pDC activation may support the control of viral replication through IFN-I production, but also improve the induction of a global immune response. Therefore, pDC activation could play a role in the control of LASV infection. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Bovine Herpesvirus Type 4 (BoHV-4) Vector Delivering Nucleocapsid Protein of Crimean-Congo Hemorrhagic Fever Virus Induces Comparable Protective Immunity against Lethal Challenge in IFNα/β/γR−/− Mice Models
Viruses 2019, 11(3), 237; https://doi.org/10.3390/v11030237 - 09 Mar 2019
Cited by 5
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a tick-borne infection with a significant mortality rate of up to 40% in endemic areas, with evidence of geographical expansion. Due to a lack of effective therapeutics and control measures, the development of [...] Read more.
Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a tick-borne infection with a significant mortality rate of up to 40% in endemic areas, with evidence of geographical expansion. Due to a lack of effective therapeutics and control measures, the development of a protective CCHFV vaccine remains a crucial public health task. This paper describes, for the first time, a Bovine herpesvirus type 4 (BoHV-4)-based viral vector (BoHV4-∆TK-CCHFV-N) and its immunogenicity in BALB/c and protection potential in IFNα/β/γR−/− mice models in comparison with two routinely used vaccine platforms, namely, Adenovirus type 5 and a DNA vector (pCDNA3.1 myc/His A), expressing the same antigen. All vaccine constructs successfully elicited significantly elevated cytokine levels and specific antibody responses in immunized BALB/c and IFNα/β/γR−/− mice. However, despite highly specific antibody responses in both animal models, the antibodies produced were unable to neutralize the virus in vitro. In the challenge experiment, only the BoHV4-∆TK-CCHFV-N and Ad5-N constructs produced 100% protection against lethal doses of the CCHFV Ank-2 strain in IFNα/β/γR−/− mice. The delivery platforms could not be compared due to similar protection rates in IFNα/β/γR−/− mice. However, during the challenge experiment in the T cell and passive antibody transfer assay, BoHV4-∆TK-CCHFV-N was dominant, with a protection rate of 75% compared to others. In conclusion, vector-based CCHFV N protein expression constitutes an effective approach for vaccine development and BoHV-4 emerged as a strong alternative to previously used viral vectors. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Priorities, Barriers, and Facilitators towards International Guidelines for the Delivery of Supportive Clinical Care during an Ebola Outbreak: A Cross-Sectional Survey
Viruses 2019, 11(2), 194; https://doi.org/10.3390/v11020194 - 23 Feb 2019
Cited by 2
Abstract
During the Ebola outbreak, mortality reduction was attributed to multiple improvements in supportive care delivered in Ebola treatment units (ETUs). We aimed to identify high-priority supportive care measures, as well as perceived barriers and facilitators to their implementation, for patients with Ebola Virus [...] Read more.
During the Ebola outbreak, mortality reduction was attributed to multiple improvements in supportive care delivered in Ebola treatment units (ETUs). We aimed to identify high-priority supportive care measures, as well as perceived barriers and facilitators to their implementation, for patients with Ebola Virus Disease (EVD). We conducted a cross-sectional survey of key stakeholders involved in the response to the 2014–2016 West African EVD outbreak. Out of 57 email invitations, 44 responses were received, and 29 respondents completed the survey. The respondents listed insufficient numbers of health workers (23/29, 79%), improper tools for the documentation of clinical data (n = 22/28, 79%), insufficient material resources (n = 22/29, 76%), and unadapted personal protective equipment (n = 20/28, 71%) as the main barriers to the provision of supportive care in ETUs. Facilitators to the provision of supportive care included team camaraderie (n in agreement = 25/28, 89%), ability to speak the local language (22/28, 79%), and having treatment protocols in place (22/28, 79%). This survey highlights a consensus across various stakeholders involved in the response to the 2014–2016 EVD outbreak on a limited number of high-priority supportive care interventions for clinical practice guidelines. Identified barriers and facilitators further inform the application of guidelines. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Co-Delivery Effect of CD24 on the Immunogenicity and Lethal Challenge Protection of a DNA Vector Expressing Nucleocapsid Protein of Crimean Congo Hemorrhagic Fever Virus
Viruses 2019, 11(1), 75; https://doi.org/10.3390/v11010075 - 17 Jan 2019
Cited by 5
Abstract
Crimean Congo hemorrhagic fever virus (CCHFV) is the causative agent of a globally-spread tick-borne zoonotic infection, with an eminent risk of fatal human disease. The imminent public health threat posed by the disseminated virus activity and lack of an approved therapeutic make CCHFV [...] Read more.
Crimean Congo hemorrhagic fever virus (CCHFV) is the causative agent of a globally-spread tick-borne zoonotic infection, with an eminent risk of fatal human disease. The imminent public health threat posed by the disseminated virus activity and lack of an approved therapeutic make CCHFV an urgent target for vaccine development. We described the construction of a DNA vector expressing a nucleocapsid protein (N) of CCHFV (pV-N13), and investigated its potential to stimulate the cytokine and total/specific antibody responses in BALB/c and a challenge experiment in IFNAR−/− mice. Because of a lack of sufficient antibody stimulation towards the N protein, we have selected cluster of differentiation 24 (CD24) protein as a potential adjuvant, which has a proliferative effect on B and T cells. Overall, our N expressing construct, when administered solely or in combination with the pCD24 vector, elicited significant cellular and humoral responses in BALB/c, despite variations in the particular cytokines and total antibodies. However, the stimulated antibodies produced as a result of the N protein expression have shown no neutralizing ability in the virus neutralization assay. Furthermore, the challenge experiments revealed the protection potential of the N expressing construct in an IFNAR −/− mice model. The cytokine analysis in the IFNAR−/− mice showed an elevation in the IL-6 and TNF-alpha levels. In conclusion, we have shown that targeting the S segment of CCHFV can be considered for a practical way to develop a vaccine against this virus, because of its ability to induce an immune response, which leads to protection in the challenge assays in the interferon (IFN)-gamma defective mice models. Moreover, CD24 has a prominent immunologic effect when it co-delivers with a suitable foreign gene expressing vector. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessArticle
Phylodynamic Analysis of Ebola Virus Disease Transmission in Sierra Leone
Viruses 2019, 11(1), 71; https://doi.org/10.3390/v11010071 - 16 Jan 2019
Cited by 2
Abstract
We generated genome sequences from 218 cases of Ebola virus disease (EVD) in Sierra Leone (SLE) during 2014–2015 to complement available datasets, particularly by including cases from a period of low sequence coverage during peak transmission of Ebola virus (EBOV) in the highly-affected [...] Read more.
We generated genome sequences from 218 cases of Ebola virus disease (EVD) in Sierra Leone (SLE) during 2014–2015 to complement available datasets, particularly by including cases from a period of low sequence coverage during peak transmission of Ebola virus (EBOV) in the highly-affected Western Area division of SLE. The combined dataset was utilized to produce phylogenetic and phylodynamic inferences, to study sink–source dynamics and virus dispersal from highly-populated transmission hotspots. We identified four districts in SLE where EBOV was introduced and transmission occurred without onward exportation to other districts. We also identified six districts that substantially contributed to the dispersal of the virus and prolonged the EVD outbreak: five of these served as major hubs, with lots of movement in and out, and one acted primarily as a source, exporting the virus to other areas of the country. Positive correlations between case numbers, inter-district transition events, and district population sizes reaffirm that population size was a driver of EBOV transmission dynamics in SLE. The data presented here confirm the role of urban hubs in virus dispersal and of a delayed laboratory response in the expansion and perpetuation of the EVD outbreak in SLE. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Review

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Open AccessReview
The Role of Reference Materials in the Research and Development of Diagnostic Tools and Treatments for Haemorrhagic Fever Viruses
Viruses 2019, 11(9), 781; https://doi.org/10.3390/v11090781 - 24 Aug 2019
Abstract
Following the Ebola outbreak in Western Africa in 2013–16, a global effort has taken place for preparedness for future outbreaks. As part of this response, the development of vaccines, treatments and diagnostic tools has been accelerated, especially towards pathogens listed as likely to [...] Read more.
Following the Ebola outbreak in Western Africa in 2013–16, a global effort has taken place for preparedness for future outbreaks. As part of this response, the development of vaccines, treatments and diagnostic tools has been accelerated, especially towards pathogens listed as likely to cause an epidemic and for which there are no current treatments. Several of the priority pathogens identified by the World Health Organisation are haemorrhagic fever viruses. This review provides information on the role of reference materials as an enabling tool for the development and evaluation of assays, and ultimately vaccines and treatments. The types of standards available are described, along with how they can be applied for assay harmonisation through calibration as a relative potency to a common arbitrary unitage system (WHO International Unit). This assures that assay metrology is accurate and robust. We describe reference materials that have been or are being developed for haemorrhagic fever viruses and consider the issues surrounding their production, particularly that of biosafety where the viruses require specialised containment facilities. Finally, we advocate the use of reference materials at early stages, including research and development, as this helps produce reliable assays and can smooth the path to regulatory approval. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessReview
Pulmonary Involvement during the Ebola Virus Disease
Viruses 2019, 11(9), 780; https://doi.org/10.3390/v11090780 - 24 Aug 2019
Abstract
Filoviruses have become a worldwide public health concern, especially during the 2013–2016 Western Africa Ebola virus disease (EVD) outbreak—the largest outbreak, both by number of cases and geographical extension, recorded so far in medical history. EVD is associated with pathologies in several organs, [...] Read more.
Filoviruses have become a worldwide public health concern, especially during the 2013–2016 Western Africa Ebola virus disease (EVD) outbreak—the largest outbreak, both by number of cases and geographical extension, recorded so far in medical history. EVD is associated with pathologies in several organs, including the liver, kidney, and lung. During the 2013–2016 Western Africa outbreak, Ebola virus (EBOV) was detected in the lung of infected patients suggesting a role in lung pathogenesis. However, little is known about lung pathogenesis and the controversial issue of aerosol transmission in EVD. This review highlights the pulmonary involvement in EVD, with a special focus on the new data emerging from the 2013–2016 Ebola outbreak. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessReview
Animal Models for Crimean-Congo Hemorrhagic Fever Human Disease
Viruses 2019, 11(7), 590; https://doi.org/10.3390/v11070590 - 28 Jun 2019
Cited by 5
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is an important tick-borne human pathogen endemic throughout Asia, Africa and Europe. CCHFV is also an emerging virus, with recent outbreaks in Western Europe. CCHFV can infect a large number of wild and domesticated mammalian species and some [...] Read more.
Crimean-Congo hemorrhagic fever virus (CCHFV) is an important tick-borne human pathogen endemic throughout Asia, Africa and Europe. CCHFV is also an emerging virus, with recent outbreaks in Western Europe. CCHFV can infect a large number of wild and domesticated mammalian species and some avian species, however the virus does not cause severe disease in these animals, but can produce viremia. In humans, CCHFV infection can lead to a severe, life-threating disease characterized by hemodynamic instability, hepatic injury and neurological disorders, with a worldwide lethality rate of ~20–30%. The pathogenic mechanisms of CCHF are poorly understood, largely due to the dearth of animal models. However, several important animal models have been recently described, including novel murine models and a non-human primate model. In this review, we examine the current knowledge of CCHF-mediated pathogenesis and describe how animal models are helping elucidate the molecular and cellular determinants of disease. This information should serve as a reference for those interested in CCHFV animal models and their utility for evaluation of medical countermeasures (MCMs) and in the study of pathogenesis. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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Open AccessBrief Report
Clinical Evaluation of QuickNaviTM-Ebola in the 2018 Outbreak of Ebola Virus Disease in the Democratic Republic of the Congo
Viruses 2019, 11(7), 589; https://doi.org/10.3390/v11070589 - 28 Jun 2019
Cited by 3
Abstract
The recent large outbreaks of Ebola virus disease (EVD) in West Africa and the Democratic Republic of the Congo (DRC) have highlighted the need for rapid diagnostic tests to control this disease. In this study, we clinically evaluated a previously developed immunochromatography-based kit, [...] Read more.
The recent large outbreaks of Ebola virus disease (EVD) in West Africa and the Democratic Republic of the Congo (DRC) have highlighted the need for rapid diagnostic tests to control this disease. In this study, we clinically evaluated a previously developed immunochromatography-based kit, QuickNaviTM-Ebola. During the 2018 outbreaks in DRC, 928 blood samples from EVD-suspected cases were tested with QuickNaviTM-Ebola and the WHO-approved GeneXpert. The sensitivity and specificity of QuickNaviTM-Ebola, estimated by comparing it to GeneXpert-confirmed cases, were 85% (68/80) and 99.8% (846/848), respectively. These results indicate the practical reliability of QuickNaviTM-Ebola for point-of-care diagnosis of EVD. Full article
(This article belongs to the Special Issue Medical Advances in Viral Hemorrhagic Fever Research)
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