Special Issue "Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures"

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

Deadline for manuscript submissions: closed (31 December 2020).

Special Issue Editors

Dr. Andrea Marzi
E-Mail Website
Guest Editor
Laboratory of Virology, DIR, NIAID, NIH, 903 South 4th Street, Hamilton, MT 59840, USA
Interests: highly pathogenic viruses; filoviruses; pathogenesis; animal models; vaccines; therapeutics; host–pathogen interactions
Prof. Dr. Chad Mire
E-Mail Website
Guest Editor
Galveston National Laboratory, University of Texas Medical Branch, 300 University Boulevard, Galveston, TX 77555, USA
Interests: lethal human viruses; henipaviruses; pathogenesis; host–pathogen interactions; vaccines; therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Infectious disease outbreaks, in particular viral hemorrhagic fever outbreaks, have increased in frequency over the last decade. New pathogens have emerged and known ones have caused outbreaks elsewhere, increasing their endemic areas. There are only a few licensed vaccines and therapeutics available to date to counter these pathogens, and more efforts are needed to increase preparedness for known and unknown emerging infectious disease outbreaks.

In this Special Issue, we wish to publish reviews and research articles documenting the current knowledge about hemorrhagic fever viruses. We are encouraging manuscripts addressing aspects of human disease and pathogenesis, the public health impact and epidemiology, the ecology and potential reservoir species, as well as the mode of transmission, animal model development, and the status of countermeasure development including vaccines, therapeutics, and diagnostics.

Dr. Andrea Marzi
Dr. Chad Mire
Guest Editors

Manuscript Submission Information

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Keywords

  • highly pathogenic viruses
  • viral hemorrhagic fever
  • animal models
  • host–pathogen interactions
  • vaccines
  • therapeutics
  • diagnostics

Published Papers (19 papers)

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Research

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Article
Transcriptomic Analysis Reveals Host miRNAs Correlated with Immune Gene Dysregulation during Fatal Disease Progression in the Ebola Virus Cynomolgus Macaque Disease Model
Microorganisms 2021, 9(3), 665; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9030665 - 23 Mar 2021
Cited by 1 | Viewed by 790
Abstract
Ebola virus is a continuing threat to human populations, causing a virulent hemorrhagic fever disease characterized by dysregulation of both the innate and adaptive host immune responses. Severe cases are distinguished by an early, elevated pro-inflammatory response followed by a pronounced lymphopenia with [...] Read more.
Ebola virus is a continuing threat to human populations, causing a virulent hemorrhagic fever disease characterized by dysregulation of both the innate and adaptive host immune responses. Severe cases are distinguished by an early, elevated pro-inflammatory response followed by a pronounced lymphopenia with B and T cells unable to mount an effective anti-viral response. The precise mechanisms underlying the dysregulation of the host immune system are poorly understood. In recent years, focus on host-derived miRNAs showed these molecules to play an important role in the host gene regulation arsenal. Here, we describe an investigation of RNA biomarkers in the fatal Ebola virus disease (EVD) cynomolgus macaque model. We monitored both host mRNA and miRNA responses in whole blood longitudinally over the disease course in these non-human primates (NHPs). Analysis of the interactions between these classes of RNAs revealed several miRNA markers significantly correlated with downregulation of genes; specifically, the analysis revealed those involved in dysregulated immune pathways associated with EVD. In particular, we noted strong interactions between the miRNAs hsa-miR-122-5p and hsa-miR-125b-5p with immunological genes regulating both B and T-cell activation. This promising set of biomarkers will be useful in future studies of severe EVD pathogenesis in both NHPs and humans and may serve as potential prognostic targets. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Space-Time Trends in Lassa Fever in Sierra Leone by ELISA Serostatus, 2012–2019
Microorganisms 2021, 9(3), 586; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9030586 - 12 Mar 2021
Viewed by 586
Abstract
Lassa fever (LF) is a viral hemorrhagic disease found in Sub-Saharan Africa and is responsible for up to 300,000 cases and 5000 deaths annually. LF is highly endemic in Sierra Leone, particularly in its Eastern Province. Kenema Government Hospital (KGH) maintains one of [...] Read more.
Lassa fever (LF) is a viral hemorrhagic disease found in Sub-Saharan Africa and is responsible for up to 300,000 cases and 5000 deaths annually. LF is highly endemic in Sierra Leone, particularly in its Eastern Province. Kenema Government Hospital (KGH) maintains one of only a few LF isolation facilities in the world with year-round diagnostic testing. Here we focus on space-time trends for LF occurring in Sierra Leone between 2012 and 2019 to provide a current account of LF in the wake of the 2014–2016 Ebola epidemic. Data were analyzed for 3277 suspected LF cases and classified as acute, recent, and non-LF or prior LF exposure using enzyme-linked immunosorbent assays (ELISAs). Presentation rates for acute, recent, and non-LF or prior LF exposure were 6.0% (195/3277), 25.6% (838/3277), and 68.4% (2244/3277), respectively. Among 2051 non-LF or prior LF exposures, 33.2% (682/2051) tested positive for convalescent LF exposure. The overall LF case-fatality rate (CFR) was 78.5% (106/135). Both clinical presentations and confirmed LF cases declined following the Ebola epidemic. These declines coincided with an increased duration between illness onset and clinical presentation, perhaps suggesting more severe disease or presentation at later stages of illness. Acute LF cases and their corresponding CFRs peaked during the dry season (November to April). Subjects with recent (but not acute) LF exposure were more likely to present during the rainy season (May to October) than the dry season (p < 0.001). The findings here suggest that LF remains endemic in Sierra Leone and that caseloads are likely to resume at levels observed prior to the Ebola epidemic. The results provide insight on the current epidemiological profile of LF in Sierra Leone to facilitate LF vaccine studies and accentuate the need for LF cohort studies and continued advancements in LF diagnostics. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs against Ebola Virus In Vivo
Microorganisms 2021, 9(3), 566; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9030566 - 10 Mar 2021
Viewed by 1124
Abstract
Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available [...] Read more.
Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here, we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Communication
The Janus Kinase Inhibitor Ruxolitinib Prevents Terminal Shock in a Mouse Model of Arenavirus Hemorrhagic Fever
Microorganisms 2021, 9(3), 564; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9030564 - 09 Mar 2021
Viewed by 709
Abstract
Arenaviruses such as Lassa virus cause arenavirus hemorrhagic fever (AVHF), but protective vaccines and effective antiviral therapy remain unmet medical needs. Our prior work has revealed that inducible nitric oxide synthase (iNOS) induction by IFN-γ represents a key pathway to microvascular leak and [...] Read more.
Arenaviruses such as Lassa virus cause arenavirus hemorrhagic fever (AVHF), but protective vaccines and effective antiviral therapy remain unmet medical needs. Our prior work has revealed that inducible nitric oxide synthase (iNOS) induction by IFN-γ represents a key pathway to microvascular leak and terminal shock in AVHF. Here we hypothesized that Ruxolitinib, an FDA-approved JAK inhibitor known to prevent IFN-γ signaling, could be repurposed for host-directed therapy in AVHF. We tested the efficacy of Ruxolitinib in MHC-humanized (HHD) mice, which develop Lassa fever-like disease upon infection with the monkey-pathogenic lymphocytic choriomeningitis virus strain WE. Anti-TNF antibody therapy was tested as an alternative strategy owing to its expected effect on macrophage activation. Ruxolitinib but not anti-TNF antibody prevented hypothermia and terminal disease as well as pleural effusions and skin edema, which served as readouts of microvascular leak. As expected, neither treatment influenced viral loads. Intriguingly, however, and despite its potent disease-modifying activity, Ruxolitinib did not measurably interfere with iNOS expression or systemic NO metabolite levels. These findings suggest that the FDA-approved JAK-inhibitor Ruxolitinib has potential in the treatment of AVHF. Moreover, our observations indicate that besides IFN-γ-induced iNOS additional druggable pathways contribute essentially to AVHF and are amenable to host-directed therapy. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Characterization of Ebola Virus Risk to Bedside Providers in an Intensive Care Environment
Microorganisms 2021, 9(3), 498; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9030498 - 26 Feb 2021
Viewed by 963
Abstract
Background: The 2014–2016 Ebola outbreak in West Africa recapitulated that nosocomial spread of Ebola virus could occur and that health care workers were at particular risk including notable cases in Europe and North America. These instances highlighted the need for centers to better [...] Read more.
Background: The 2014–2016 Ebola outbreak in West Africa recapitulated that nosocomial spread of Ebola virus could occur and that health care workers were at particular risk including notable cases in Europe and North America. These instances highlighted the need for centers to better prepare for potential Ebola virus cases; including understanding how the virus spreads and which interventions pose the greatest risk. Methods: We created a fully equipped intensive care unit (ICU), within a Biosafety Level 4 (BSL4) laboratory, and infected multiple sedated non-human primates (NHPs) with Ebola virus. While providing bedside care, we sampled blood, urine, and gastric residuals; as well as buccal, ocular, nasal, rectal, and skin swabs, to assess the risks associated with routine care. We also assessed the physical environment at end-point. Results: Although viral RNA was detectable in blood as early as three days post-infection, it was not detectable in the urine, gastric fluid, or swabs until late-stage disease. While droplet spread and fomite contamination were present on a few of the surfaces that were routinely touched while providing care in the ICU for the infected animal, these may have been abrogated through good routine hygiene practices. Conclusions: Overall this study has helped further our understanding of which procedures may pose the highest risk to healthcare providers and provides temporal evidence of this over the clinical course of disease. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Development of a Well-Characterized Rhesus Macaque Model of Ebola Virus Disease for Support of Product Development
Microorganisms 2021, 9(3), 489; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9030489 - 26 Feb 2021
Viewed by 675
Abstract
Ebola virus (EBOV) is a negative-sense RNA virus that can infect humans and nonhuman primates with severe health consequences. Development of countermeasures requires a thorough understanding of the interaction between host and pathogen, and the course of disease. The goal of this study [...] Read more.
Ebola virus (EBOV) is a negative-sense RNA virus that can infect humans and nonhuman primates with severe health consequences. Development of countermeasures requires a thorough understanding of the interaction between host and pathogen, and the course of disease. The goal of this study was to further characterize EBOV disease in a uniformly lethal rhesus macaque model, in order to support development of a well-characterized model following rigorous quality standards. Rhesus macaques were intramuscularly exposed to EBOV and one group was euthanized at predetermined time points to characterize progression of disease. A second group was not scheduled for euthanasia in order to analyze survival, changes in physiology, clinical pathology, terminal pathology, and telemetry kinetics. On day 3, sporadic viremia was observed and pathological evidence was noted in lymph nodes. By day 5, viremia was detected in all EBOV exposed animals and pathological evidence was noted in the liver, spleen, and gastrointestinal tissues. These data support the notion that EBOV infection in rhesus macaques is a rapid systemic disease similar to infection in humans, under a compressed time scale. Biomarkers that correlated with disease progression at the earliest stages of infection were observed thereby identifying potential “trigger-to-treat” for use in therapeutic studies. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Phylogenetic Characterization of Crimean-Congo Hemorrhagic Fever Virus Detected in African Blue Ticks Feeding on Cattle in a Ugandan Abattoir
Microorganisms 2021, 9(2), 438; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9020438 - 20 Feb 2021
Cited by 1 | Viewed by 1004
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is the most geographically widespread of the tick-borne viruses. However, African strains of CCHFV are poorly represented in sequence databases. In addition, almost all sequence data collected to date have been obtained from cases of human disease, while [...] Read more.
Crimean-Congo hemorrhagic fever virus (CCHFV) is the most geographically widespread of the tick-borne viruses. However, African strains of CCHFV are poorly represented in sequence databases. In addition, almost all sequence data collected to date have been obtained from cases of human disease, while information regarding the circulation of the virus in tick and animal reservoirs is severely lacking. Here, we characterize the complete coding region of a novel CCHFV strain, detected in African blue ticks (Rhipicephalus (Boophilus) decoloratus) feeding on cattle in an abattoir in Kampala, Uganda. These cattle originated from a farm in Mbarara, a major cattle-trading hub for much of Uganda. Phylogenetic analysis indicates that the newly sequenced strain belongs to the African genotype II clade, which predominantly contains the sequences of strains isolated from West Africa in the 1950s, and South Africa in the 1980s. Whilst the viral S (nucleoprotein) and L (RNA polymerase) genome segments shared >90% nucleotide similarity with previously reported genotype II strains, the glycoprotein-coding M segment shared only 80% nucleotide similarity with the next most closely related strains, which were derived from ticks in Western India and Northern China. This genome segment also displayed a large number of non-synonymous mutations previously unreported in the genotype II strains. Characterization of this novel strain adds to our limited understanding of the natural diversity of CCHFV circulating in both ticks and in Africa. Such data can be used to inform the design of vaccines and diagnostics, as well as studies exploring the epidemiology and evolution of the virus for the establishment of future CCHFV control strategies. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Taï Forest Virus Does Not Cause Lethal Disease in Ferrets
Microorganisms 2021, 9(2), 213; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9020213 - 21 Jan 2021
Viewed by 578
Abstract
Filoviruses are zoonotic, negative-sense RNA viruses, most of which are capable of causing severe disease in humans and nonhuman primates, often with high case fatality rates. Among these viruses, those belonging to the Ebolavirus genus—particularly Ebola virus, Sudan virus, and Bundibugyo virus—represent some [...] Read more.
Filoviruses are zoonotic, negative-sense RNA viruses, most of which are capable of causing severe disease in humans and nonhuman primates, often with high case fatality rates. Among these viruses, those belonging to the Ebolavirus genus—particularly Ebola virus, Sudan virus, and Bundibugyo virus—represent some of the most pathogenic to humans. Taï Forest virus (TAFV) is thought to be among the least pathogenic ebolaviruses; however, only a single non-fatal case has been documented in humans, in 1994. With the recent success of the ferret as a lethal model for a number of ebolaviruses, we set out to evaluate its suitability as a model for TAFV. Our results demonstrate that, unlike other ebolaviruses, TAFV infection in ferrets does not result in lethal disease. None of the intramuscularly inoculated animals demonstrated any overt signs of disease, whereas the intranasally inoculated animals exhibited mild to moderate weight loss during the early stage of infection but recovered quickly. Low levels of viral RNA were detected in the blood and tissues of several animals, particularly the intranasally inoculated animals, and all animals mounted a humoral immune response, with high titers of GP-specific IgG detectable as early as 14 days post-infection. These data provide additional insight into the pathogenesis of TAFV. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Automation of Infectious Focus Assay for Determination of Filovirus Titers and Direct Comparison to Plaque and TCID50 Assays
Microorganisms 2021, 9(1), 156; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9010156 - 12 Jan 2021
Cited by 3 | Viewed by 1082
Abstract
Ongoing efforts to develop effective therapies against filoviruses rely, to different extents, on quantifying the amount of viable virus in samples by plaque, TCID50, and focus assays. Unfortunately, these techniques have inherent variance, and laboratory-specific preferences make direct comparison of data [...] Read more.
Ongoing efforts to develop effective therapies against filoviruses rely, to different extents, on quantifying the amount of viable virus in samples by plaque, TCID50, and focus assays. Unfortunately, these techniques have inherent variance, and laboratory-specific preferences make direct comparison of data difficult. Additionally, human errors such as operator errors and subjective bias can further compound the differences in outcomes. To overcome these biases, we developed a computer-based automated image-processing method for a focus assay based on the open-source CellProfiler software platform, which enables high-throughput screening of many treatment samples at one time. We compared virus titers calculated using this platform to plaque and TCID50 assays using common stocks of virus for 3 major Filovirus species, Zaire ebolavirus, Sudan ebolavirus, and Marburg marburgvirus with each assay performed by multiple operators on multiple days. We show that plaque assays give comparable findings that differ by less than 3-fold. Focus-forming unit (FFU) and TCID50 assays differ by 10-fold or less from the plaque assays due a higher (FFU) and lower (TCID50) sensitivity. However, reproducibility and accuracy of each assay differs significantly with Neutral Red Agarose Overlay plaque assays and TCID50 with the lowest reproducibility due to subjective analysis and operator error. Both crystal violet methylcellulose overlay plaque assay and focus assays perform best for accuracy and the focus assay performs best for speed and throughput. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Sheep and Cattle Are Not Susceptible to Experimental Inoculation with Hazara Orthonairovirus, a Tick-Borne Arbovirus Closely Related to CCHFV
Microorganisms 2020, 8(12), 1927; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8121927 - 04 Dec 2020
Cited by 5 | Viewed by 937
Abstract
Hazara orthonairovirus (HAZV) is a tick-borne arbovirus closely related to Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV). Whereas CCHFV is a biosafety level (BSL) 4 agent, HAZV is classified as BSL 2, as it is not known to cause any disease in humans. Belonging to [...] Read more.
Hazara orthonairovirus (HAZV) is a tick-borne arbovirus closely related to Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV). Whereas CCHFV is a biosafety level (BSL) 4 agent, HAZV is classified as BSL 2, as it is not known to cause any disease in humans. Belonging to the same serogroup as CCHFV, HAZV might act as a model which can provide a better understanding of this important zoonosis. Furthermore, the serological relatedness may cause diagnostic problems if antibodies against HAZV interfere with current CCHFV serological assays. Therefore, sheep and cattle—important natural hosts for CCHFV—were experimentally infected with HAZV to prove their susceptibility and evaluate potential antibody cross-reactivities. According to this study, neither sheep nor cattle are susceptible to experimental HAZV infections. Consequently, the HAZV infection in ruminants is clearly distinct from CCHFV infections. Sera of immunized animals weakly cross-reacted between HAZV and CCHFV in immunofluorescence and immunoblot assays, but not in commercial CCHFV ELISAs commonly used for field studies. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Development of an Enzyme-Linked Immunosorbent Assay to Determine the Expression Dynamics of Ebola Virus Soluble Glycoprotein during Infection
Microorganisms 2020, 8(10), 1535; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8101535 - 06 Oct 2020
Cited by 1 | Viewed by 684
Abstract
Ebola virus (EBOV) is a highly pathogenic virus with human case fatality rates of up to 90%. EBOV uses transcriptional editing to express three different glycoproteins (GPs) from its GP gene: soluble GP (sGP), GP, and small sGP (ssGP). The molecular ratio of [...] Read more.
Ebola virus (EBOV) is a highly pathogenic virus with human case fatality rates of up to 90%. EBOV uses transcriptional editing to express three different glycoproteins (GPs) from its GP gene: soluble GP (sGP), GP, and small sGP (ssGP). The molecular ratio of unedited to edited mRNA is about 70% (sGP): 25% (GP): 5% (ssGP), indicating that sGP is produced more abundantly than GP. While the presence of sGP has been confirmed in the blood during human EBOV infection, there is no report about its expression dynamics. In this study, we developed an EBOV-sGP-specific sandwich enzyme-linked immunosorbent assay (ELISA) using two different available antibodies and tested several animal serum samples to determine the concentration of sGP. EBOV-sGP was detected in nonhuman primate serum samples as early as 4 days after EBOV infection, correlating with RT-qPCR positivity. This ELISA might be further developed into a diagnostic tool for detection of EBOV in patients. Furthermore, this study provides insights into the expression dynamics of sGP during infection, which are important to decipher the function that sGP plays during infection. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Receptor-Mediated Host Cell Preference of a Bat-Derived Filovirus, Lloviu Virus
Microorganisms 2020, 8(10), 1530; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8101530 - 05 Oct 2020
Cited by 2 | Viewed by 911
Abstract
Lloviu virus (LLOV), a bat-derived filovirus that is phylogenetically distinct from human pathogenic filoviruses such as Ebola virus (EBOV) and Marburg virus (MARV), was discovered in Europe. However, since infectious LLOV has never been isolated, the biological properties of this virus remain poorly [...] Read more.
Lloviu virus (LLOV), a bat-derived filovirus that is phylogenetically distinct from human pathogenic filoviruses such as Ebola virus (EBOV) and Marburg virus (MARV), was discovered in Europe. However, since infectious LLOV has never been isolated, the biological properties of this virus remain poorly understood. We found that vesicular stomatitis virus (VSV) pseudotyped with the glycoprotein (GP) of LLOV (VSV–LLOV) showed higher infectivity in one bat (Miniopterus sp.)-derived cell line than in the other bat-derived cell lines tested, which was distinct from the tropism of VSV pseudotyped with EBOV (VSV–EBOV) and MARV GPs. We then focused on the interaction between GP and Niemann–Pick C1 (NPC1) protein, one of the cellular receptors of filoviruses. We introduced the Miniopterus bat and human NPC1 genes into NPC1-knockout Vero E6 cells and their susceptibilities to the viruses were compared. The cell line expressing the bat NPC1 showed higher susceptibility to VSV–LLOV than that expressing human NPC1, whereas the opposite preference was seen for VSV–EBOV. Using a site-directed mutagenesis approach, amino acid residues involved in the differential tropism were identified in the NPC1 and GP molecules. Our results suggest that the interaction between GP and NPC1 is an important factor in the tropism of LLOV to a particular bat species. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Differences in Viral RNA Synthesis but Not Budding or Entry Contribute to the In Vitro Attenuation of Reston Virus Compared to Ebola Virus
Microorganisms 2020, 8(8), 1215; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8081215 - 11 Aug 2020
Cited by 2 | Viewed by 874
Abstract
Most filoviruses cause severe disease in humans. For example, Ebola virus (EBOV) is responsible for the two most extensive outbreaks of filovirus disease to date, with case fatality rates of 66% and 40%, respectively. In contrast, Reston virus (RESTV) is apparently apathogenic in [...] Read more.
Most filoviruses cause severe disease in humans. For example, Ebola virus (EBOV) is responsible for the two most extensive outbreaks of filovirus disease to date, with case fatality rates of 66% and 40%, respectively. In contrast, Reston virus (RESTV) is apparently apathogenic in humans, and while transmission of RESTV from domestic pigs to people results in seroconversion, no signs of disease have been reported in such cases. The determinants leading to these differences in pathogenicity are not well understood, but such information is needed in order to better evaluate the risks posed by the repeated spillover of RESTV into the human population and to perform risk assessments for newly emerging filoviruses with unknown pathogenic potential. Interestingly, RESTV and EBOV already show marked differences in their growth in vitro, with RESTV growing slower and reaching lower end titers. In order to understand the basis for this in vitro attenuation of RESTV, we used various life cycle modeling systems mimicking different aspects of the virus life cycle. Our results showed that viral RNA synthesis was markedly slower when using the ribonucleoprotein (RNP) components from RESTV, rather than those for EBOV. In contrast, the kinetics of budding and entry were indistinguishable between these two viruses. These data contribute to our understanding of the molecular basis for filovirus pathogenicity by showing that it is primarily differences in the robustness of RNA synthesis by the viral RNP complex that are responsible for the impaired growth of RESTV in tissue culture. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
Prothrombin Time, Activated Partial Thromboplastin Time, and Fibrinogen Reference Intervals for Inbred Strain 13/N Guinea Pigs (Cavia porcellus) and Validation of Low Volume Sample Analysis
Microorganisms 2020, 8(8), 1127; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8081127 - 27 Jul 2020
Viewed by 787
Abstract
Inbred strain 13/N guinea pigs are used as small animal models for the study of hemorrhagic fever viruses. Coagulation abnormalities, including prolonged clotting times and bleeding, are characteristic of hemorrhagic fever in humans; patients often meet criteria for disseminated intravascular coagulation (DIC). Comprehensively [...] Read more.
Inbred strain 13/N guinea pigs are used as small animal models for the study of hemorrhagic fever viruses. Coagulation abnormalities, including prolonged clotting times and bleeding, are characteristic of hemorrhagic fever in humans; patients often meet criteria for disseminated intravascular coagulation (DIC). Comprehensively evaluating coagulation function is critical in model development and studies of viral pathogenesis and therapeutic efficacy. Here, using the VetScan VSpro veterinary point-of-care platform, we developed reference intervals in both juvenile and adult strain 13/N guinea pigs for three coagulation parameters: prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen. In addition, for situations or species with limited availability of blood for clinical analysis, we investigated the validity of a modified collection approach for low-volume (0.1 mL) blood sample analysis of PT and aPTT. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Article
The Crimean-Congo Hemorrhagic Fever Virus NSm Protein Is Dispensable for Growth In Vitro and Disease in Ifnar-/- Mice
Microorganisms 2020, 8(5), 775; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8050775 - 21 May 2020
Cited by 4 | Viewed by 1271
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tri-segmented, tick-borne nairovirus that causes disease of ranging severity in humans. The CCHFV M segment encodes a complex glycoprotein precursor (GPC) that undergoes extensive endoproteolytic cleavage, giving rise to two structural proteins (Gn and Gc) required [...] Read more.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tri-segmented, tick-borne nairovirus that causes disease of ranging severity in humans. The CCHFV M segment encodes a complex glycoprotein precursor (GPC) that undergoes extensive endoproteolytic cleavage, giving rise to two structural proteins (Gn and Gc) required for virus attachment and entry, and to multiple non-structural proteins (NSm, GP160, GP85, and GP38). The functions of these non-structural proteins remain largely unclear. Here, we investigate the role of NSm during infection by generating a recombinant CCHFV lacking the complete NSm domain (10200∆NSm) and observing CCHFV ∆NSm replication in cell lines and pathogenicity in Ifnar-/- mice. Our data demonstrate that the NSm domain is dispensable for viral replication in vitro, and, despite the delayed onset of clinical signs, CCHFV lacking this domain caused severe or lethal disease in infected mice. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Review

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Review
Lassa Virus Treatment Options
Microorganisms 2021, 9(4), 772; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9040772 - 07 Apr 2021
Cited by 3 | Viewed by 724
Abstract
Lassa fever causes an approximate 5000 to 10,000 deaths annually in West Africa and cases have been imported into Europe and the Americas, challenging public health. Although Lassa virus was first described over 5 decades ago in 1969, no treatments or vaccines have [...] Read more.
Lassa fever causes an approximate 5000 to 10,000 deaths annually in West Africa and cases have been imported into Europe and the Americas, challenging public health. Although Lassa virus was first described over 5 decades ago in 1969, no treatments or vaccines have been approved to treat or prevent infection. In this review, we discuss current therapeutics in the development pipeline for the treatment of Lassa fever, focusing on those that have been evaluated in humans or animal models. Several treatments, including the antiviral favipiravir and a human monoclonal antibody cocktail, have shown efficacy in preclinical rodent and non-human primate animal models and have potential for use in clinical settings. Movement of the promising preclinical treatment options for Lassa fever into clinical trials is critical to continue addressing this neglected tropical disease. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
Review
Epidemiological Aspects of Crimean-Congo Hemorrhagic Fever in Western Europe: What about the Future?
Microorganisms 2021, 9(3), 649; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms9030649 - 21 Mar 2021
Cited by 5 | Viewed by 1064
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is an arthropod-borne virus (arbovirus), mainly transmitted by ticks, belonging to the genus Orthonairovirus (family Nairoviridae, order Bunyavirales). CCHFV causes a potentially severe, or even fatal, human disease, and it is widely distributed in Africa, Asia, [...] Read more.
Crimean-Congo hemorrhagic fever virus (CCHFV) is an arthropod-borne virus (arbovirus), mainly transmitted by ticks, belonging to the genus Orthonairovirus (family Nairoviridae, order Bunyavirales). CCHFV causes a potentially severe, or even fatal, human disease, and it is widely distributed in Africa, Asia, eastern Europe and, more recently, in South-western Europe. Until a few years ago, no cases of Crimean-Congo hemorrhagic fever (CCHF) had been reported in western Europe, with the exception of several travel-associated cases. In 2010, the CCHFV was reported for the first time in South-western Europe when viral RNA was obtained from Hyalomma lusitanicum ticks collected from deer in Cáceres (Spain). Migratory birds from Africa harboring CCHFV-infected ticks and flying to Spain appear to have contributed to the establishment of the virus (genotype III, Africa-3) in this country. In addition, the recent findings in a patient and in ticks from deer and wild boar of viral sequences similar to those from eastern Europe (genotype V, Europe-1), raise the possibility of the introduction of CCHFV into Spain through the animal trade, although the arrival by bird routes cannot be ruled out (Africa-4 has been also recently detected). The seropositive rates of animals detected in regions of South-western Spain suggest an established cycle of tick-host-tick in certain areas, and the segment reassortment detected in the sequenced virus from one patient evidences a high ability to adaptation of the virus. Different ixodid tick genera can be vectors and reservoirs of the virus, although Hyalomma spp. are particularly relevant for its maintenance. This tick genus is common in Mediterranean region but it is currently spreading to new areas, partly due to the climate change and movement of livestock or wild animals. Although to a lesser extent, travels with our pets (and their ticks) may be also a factor to be considered. As a consequence, the virus is expanding from the Balkan region to Central Europe and, more recently, to Western Europe where different genotypes are circulating. Thus, seven human cases confirmed by molecular methods have been reported in Spain from 2016 to August 2020, three of them with a fatal outcome. A One Health approach is essential for the surveillance of fauna and vector populations to assess the risk for humans and animals. We discuss the risk of CCHFV causing epidemic outbreaks in Western Europe. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Review
To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity
Microorganisms 2020, 8(10), 1473; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8101473 - 25 Sep 2020
Cited by 6 | Viewed by 1099
Abstract
Zaire Ebola virus (EBOV) is a member of the Filoviridae family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first [...] Read more.
Zaire Ebola virus (EBOV) is a member of the Filoviridae family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first vaccine against EBOV, a recombinant live-attenuated viral vector wherein the G protein of vesicular stomatitis virus is replaced with the glycoprotein (GP) of EBOV (rVSV-EBOV-GP, Ervebo® by Merck). This vaccine demonstrates high efficacy in nonhuman primates by providing prophylactic, rapid, and post-exposure protection. In humans, rVSV-EBOV-GP demonstrated 100% protection in several phase III clinical trials in over 10,000 individuals during the 2013–2016 West Africa epidemic. As of 2020, over 218,000 doses of rVSV-EBOV-GP have been administered to individuals with high risk of EBOV exposure. Despite licensure and robust preclinical studies, the mechanisms of rVSV-EBOV-GP-mediated protection are not fully understood. Such knowledge is crucial for understanding vaccine-mediated correlates of protection from EVD and to aid the further design and development of therapeutics against filoviruses. Here, we summarize the current literature regarding the host response to vaccination and EBOV exposure, and evidence regarding innate and adaptive immune mechanisms involved in rVSV-EBOV-GP-mediated protection, with a focus on the host transcriptional response. Current data strongly suggest a protective synergy between rapid innate and humoral immunity. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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Review
Kyasanur Forest Disease and Alkhurma Hemorrhagic Fever Virus—Two Neglected Zoonotic Pathogens
Microorganisms 2020, 8(9), 1406; https://0-doi-org.brum.beds.ac.uk/10.3390/microorganisms8091406 - 12 Sep 2020
Cited by 4 | Viewed by 1174
Abstract
Kyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic fever virus (AHFV) are tick-borne flaviviruses that cause life-threatening hemorrhagic fever in humans with case fatality rates of 3–5% for KFDV and 1–20% for AHFV, respectively. Both viruses are biosafety level 4 pathogens due to [...] Read more.
Kyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic fever virus (AHFV) are tick-borne flaviviruses that cause life-threatening hemorrhagic fever in humans with case fatality rates of 3–5% for KFDV and 1–20% for AHFV, respectively. Both viruses are biosafety level 4 pathogens due to the severity of disease they cause and the lack of effective countermeasures. KFDV was discovered in India and is restricted to parts of the Indian subcontinent, whereas AHFV has been found in Saudi Arabia and Egypt. In recent years, both viruses have spread beyond their original endemic zones and the potential of AHFV to spread through ticks on migratory birds is a public health concern. While there is a vaccine with limited efficacy for KFDV used in India, there is no vaccine for AHFV nor are there any therapeutic concepts to combat infections with these viruses. In this review, we summarize the current knowledge about pathogenesis, vector distribution, virus spread, and infection control. We aim to bring attention to the potential public health threats posed by KFDV and AHFV and highlight the urgent need for the development of effective countermeasures. Full article
(This article belongs to the Special Issue Hemorrhagic Fever Viruses: Pathogenesis and Countermeasures)
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