Immunocompetent Mouse Model for Crimean-Congo Hemorrhagic Fever Virus

AbstractCrimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne febrile illness with wide geographic distribution. CCHF is caused by infection with the Crimean-Congo hemorrhagic fever virus (CCHFV) and case fatality rates can be as high as 30%. Despite causing severe disease in humans, our understanding of the host and viral determinants of CCHFV pathogenesis are limited. A major limitation in the investigation of CCHF has been the lack of suitable small animal models. Wild-type mice are resistant to clinical isolates of CCHFV and consequently, mice must be deficient in type I interferon responses to study the more severe aspects of CCHFV. We report here a mouse-adapted variant of CCHFV that recapitulates in adult, immunocompetent mice the severe CCHF observed in humans. This mouse-adapted variant of CCHFV significantly improves our ability to study host and viral determinants of CCHFV-induced disease in a highly tractable mouse model.

Download Full-text

Immunocompetent mouse model for Crimean-Congo hemorrhagic fever virus

eLife ◽

10.7554/elife.63906 ◽

2021 ◽

Vol 10 ◽

Author(s):

David W Hawman ◽

Kimberly Meade-White ◽

Shanna Leventhal ◽

Friederike Feldmann ◽

Atsushi Okumura ◽

...

Keyword(s):

Mouse Model ◽

Severe Disease ◽

Case Fatality ◽

Febrile Illness ◽

Hemorrhagic Fever ◽

Fever Virus ◽

Type I ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus ◽

Viral Determinants

Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne febrile illness with wide geographic distribution. CCHF is caused by infection with the Crimean-Congo hemorrhagic fever virus (CCHFV) and case fatality rates can be as high as 30%. Despite causing severe disease in humans, our understanding of the host and viral determinants of CCHFV pathogenesis are limited. A major limitation in the investigation of CCHF has been the lack of suitable small animal models. Wild-type mice are resistant to clinical isolates of CCHFV and consequently, mice must be deficient in type I interferon responses to study the more severe aspects of CCHFV. We report here a mouse-adapted variant of CCHFV that recapitulates in adult, immunocompetent mice the severe CCHF observed in humans. This mouse-adapted variant of CCHFV significantly improves our ability to study host and viral determinants of CCHFV-induced disease in a highly tractable mouse model.

Download Full-text

T-Cells and Interferon Gamma Are Necessary for Survival Following Crimean-Congo Hemorrhagic Fever Virus Infection in Mice

Microorganisms ◽

10.3390/microorganisms9020279 ◽

2021 ◽

Vol 9 (2) ◽

pp. 279

Author(s):

David W. Hawman ◽

Kimberly Meade-White ◽

Shanna Leventhal ◽

Aaron Carmody ◽

Elaine Haddock ◽

...

Keyword(s):

T Cells ◽

Interferon Gamma ◽

Severe Disease ◽

Adaptive Immune Response ◽

Case Fatality ◽

Febrile Illness ◽

Hemorrhagic Fever ◽

Fever Virus ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus

Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne febrile illness with wide geographic distribution. In humans, the disease follows infection by the Crimean-Congo hemorrhagic fever virus (CCHFV) and begins as flu-like symptoms that can rapidly progress to hemorrhaging and death. Case fatality rates can be as high as 30%. An important gap in our understanding of CCHF are the host immune responses necessary to control the infection. A better understanding of these responses is needed to direct therapeutic strategies to limit the often-severe morbidity and mortality seen in humans. In this report, we have utilized a mouse model in which mice develop severe disease but ultimately recover. T-cells were robustly activated, differentiated to produce antiviral cytokines, and were critical for survival following CCHFV infection. We further identified a key role for interferon gamma (IFNγ) in survival following CCHFV infection. These results significantly improve our understanding of the host adaptive immune response to severe CCHFV infection.

Download Full-text

Pathogenesis and Immune Response of Crimean-Congo Hemorrhagic Fever Virus in a STAT-1 Knockout Mouse Model

Journal of Virology ◽

10.1128/jvi.01383-10 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11089-11100 ◽

Cited By ~ 139

Author(s):

Dennis A. Bente ◽

Judie B. Alimonti ◽

Wun-Ju Shieh ◽

Gaëlle Camus ◽

Ute Ströher ◽

...

Keyword(s):

Animal Model ◽

Mouse Model ◽

Immune Cell ◽

Hemorrhagic Fever ◽

Fever Virus ◽

Interferon Response ◽

Laboratory Animals ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus ◽

Elevated Liver Enzymes

ABSTRACT Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) causes a severe hemorrhagic syndrome in humans but not in its vertebrate animal hosts. The pathogenesis of the disease is largely not understood due to the lack of an animal model. Laboratory animals typically show no overt signs of disease. Here, we describe a new small-animal model to study CCHFV pathogenesis that manifests clinical disease, similar to that seen in humans, without adaptation of the virus to the host. Our studies revealed that mice deficient in the STAT-1 signaling molecule were highly susceptible to infection, succumbing within 3 to 5 days. After CCHFV challenge, mice exhibited fever, leukopenia, thrombocytopenia, and highly elevated liver enzymes. Rapid viremic dissemination and extensive replication in visceral organs, mainly in liver and spleen, were associated with prominent histopathologic changes in these organs. Dramatically elevated proinflammatory cytokine levels were detected in the blood of the animals, suggestive of a cytokine storm. Immunologic analysis revealed delayed immune cell activation and intensive lymphocyte depletion. Furthermore, this study also demonstrated that ribavirin, a suggested treatment in human cases, protects mice from lethal CCHFV challenge. In conclusion, our data demonstrate that the interferon response is crucial in controlling CCHFV replication in this model, and this is the first study that offers an in-depth in vivo analysis of CCHFV pathophysiology. This new mouse model exhibits key features of fatal human CCHF, proves useful for the testing of therapeutic strategies, and can be used to study virus attenuation.

Download Full-text

Type I interferon inhibits Crimean-Congo hemorrhagic fever virus in human target cells

Journal of Medical Virology ◽

10.1002/jmv.20530 ◽

2005 ◽

Vol 78 (2) ◽

pp. 216-222 ◽

Cited By ~ 42

Author(s):

Ida Andersson ◽

Åke Lundkvist ◽

Otto Haller ◽

Ali Mirazimi

Keyword(s):

Type I Interferon ◽

Hemorrhagic Fever ◽

Fever Virus ◽

Target Cells ◽

Type I ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus

Download Full-text

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38

Journal of Virology ◽

10.1128/jvi.02005-19 ◽

2020 ◽

Vol 94 (8) ◽

Author(s):

Akaash K. Mishra ◽

Crystal L. Moyer ◽

Dafna M. Abelson ◽

Daniel J. Deer ◽

Kamel El Omari ◽

...

Keyword(s):

Crystal Structure ◽

Gene Duplication ◽

Mouse Model ◽

Hemorrhagic Fever ◽

Duplication Event ◽

Fever Virus ◽

Gene Duplication Event ◽

Protective Antibody ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of the most widespread tick-borne viral infection in humans. CCHFV encodes a secreted glycoprotein (GP38) of unknown function that is the target of a protective antibody. Here, we present the crystal structure of GP38 at a resolution of 2.5 Å, which revealed a novel fold primarily consisting of a 3-helix bundle and a β-sandwich. Sequence alignment and homology modeling showed distant homology between GP38 and the ectodomain of Gn (a structural glycoprotein in CCHFV), suggestive of a gene duplication event. Analysis of convalescent-phase sera showed high titers of GP38 antibodies indicating immunogenicity in humans during natural CCHFV infection. The only protective antibody for CCHFV in an adult mouse model reported to date, 13G8, bound GP38 with subnanomolar affinity and protected against heterologous CCHFV challenge in a STAT1-knockout mouse model. Our data strongly suggest that GP38 should be evaluated as a vaccine antigen and that its structure provides a foundation to investigate functions of this protein in the viral life cycle. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen that poses a high risk to public health. Due to the high morbidity and mortality rates associated with CCHFV infection, there is an urgent need to develop medical countermeasures for disease prevention and treatment. CCHFV GP38, a secreted glycoprotein of unknown function unique to the Nairoviridae family, was recently shown to be the target of a protective antibody against CCHFV. Here, we present the crystal structure of GP38, which revealed a novel fold with distant homology to another CCHFV glycoprotein that is suggestive of a gene duplication event. We also demonstrate that antibody 13G8 protects STAT1-knockout mice against heterologous CCHFV challenge using a clinical isolate from regions where CCHFV is endemic. Collectively, these data advance our understanding of GP38 structure and antigenicity and should facilitate future studies investigating its function.

Download Full-text

Worldwide epidemiology of Crimean-Congo Hemorrhagic Fever Virus in humans, ticks and other animal species, a systematic review and meta-analysis

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009299 ◽

2021 ◽

Vol 15 (4) ◽

pp. e0009299

Author(s):

Jean Thierry Ebogo Belobo ◽

Sebastien Kenmoe ◽

Cyprien Kengne-Nde ◽

Cynthia Paola Demeni Emoh ◽

Arnol Bowo-Ngandji ◽

...

Keyword(s):

Systematic Review ◽

Low Income ◽

Animal Species ◽

Meta Analysis ◽

Random Effect ◽

Case Fatality ◽

Hemorrhagic Fever ◽

Fever Virus ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus

There are uncertainties about the global epidemiological data of infections due to Crimean-Congo hemorrhagic fever virus (CCHFV). We estimated the global case fatality rate (CFR) of CCHFV infections and the prevalence of CCHFV in humans, ticks and other animal species. We also explored the socio-demographic and clinical factors that influence these parameters. In this systematic review with meta–analyses we searched publications from database inception to 03rd February 2020 in Pubmed, Scopus, and Global Index Medicus. Studies included in this review provided cross-sectional data on the CFR and/or prevalence of one or more targets used for the detection of CCHFV. Two independent investigators selected studies to be included. Data extraction and risk of bias assessment were conducted independently by all authors. Data collected were analysed using a random effect meta-analysis. In all, 2345 records were found and a total of 312 articles (802 prevalence and/or CFR data) that met the inclusion criteria were retained. The overall CFR was 11.7% (95% CI = 9.1–14.5), 8.0% (95% CI = 1.0–18.9), and 4.7% (95% CI = 0.0–37.6) in humans with acute, recent, and past CCHFV infections respectively. The overall CCHFV acute infections prevalence was 22.5% (95% CI = 15.7–30.1) in humans, 2.1% (95% CI = 1.3–2.9) in ticks, and 4.5% (95% CI = 1.9–7.9) in other animal species. The overall CCHFV recent infections seroprevalence was 11.6% (95% CI = 7.9–16.4) in humans and 0.4% (95% CI = 0.0–2.9) in other animal species. The overall CCHFV past infections seroprevalence was 4.3% (95% CI = 3.3–5.4) in humans and 12.0% (95% CI = 9.9–14.3) in other animal species. CFR was higher in low-income countries, countries in the WHO African, South-East Asia and Eastern Mediterranean regions, in adult and ambulatory patients. CCHFV detection rate in humans were higher in CCHFV suspected cases, healthcare workers, adult and hospitalized patients, ticks of the genus Ornithodoros and Amblyomma and in animals of the orders Perissodactyla and Bucerotiformes. This review highlights a significant disease burden due to CCHFV with a strong disparity according to country income levels, geographic regions, various human categories and tick and other animal species. Preventive measures in the light of these findings are expected.

Download Full-text

GP38-targeting monoclonal antibodies protect adult mice against lethal Crimean-Congo hemorrhagic fever virus infection

Science Advances ◽

10.1126/sciadv.aaw9535 ◽

2019 ◽

Vol 5 (7) ◽

pp. eaaw9535 ◽

Cited By ~ 10

Author(s):

Joseph W. Golden ◽

Charles J. Shoemaker ◽

Michael E. Lindquist ◽

Xiankun Zeng ◽

Sharon P. Daye ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Neutralizing Antibodies ◽

Protective Efficacy ◽

Hemorrhagic Fever ◽

Fever Virus ◽

Type I ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus ◽

Adult Mice ◽

Virus Exposure

Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. Limited evidence suggests that antibodies can protect humans against lethal CCHFV disease but the protective efficacy of antibodies has never been evaluated in adult animal models. Here, we used adult mice to investigate the protection provided against CCHFV infection by glycoprotein-targeting neutralizing and non-neutralizing monoclonal antibodies (mAbs). We identified a single non-neutralizing antibody (mAb-13G8) that protected adult type I interferon–deficient mice >90% when treatment was initiated before virus exposure and >60% when administered after virus exposure. Neutralizing antibodies known to protect neonatal mice from lethal CCHFV infection failed to confer protection regardless of immunoglobulin G subclass. The target of mAb-13G8 was identified as GP38, one of multiple proteolytically cleaved glycoproteins derived from the CCHFV glycoprotein precursor polyprotein. This study reveals GP38 as an important antibody target for limiting CCHFV pathogenesis and lays the foundation to develop immunotherapeutics against CCHFV in humans.

Download Full-text

Crimean-Congo Hemorrhagic Fever Mouse Model Recapitulating Human Convalescence

Journal of Virology ◽

10.1128/jvi.00554-19 ◽

2019 ◽

Vol 93 (18) ◽

Cited By ~ 4

Author(s):

David W. Hawman ◽

Kimberly Meade-White ◽

Elaine Haddock ◽

Rumi Habib ◽

Dana Scott ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

Immune Responses ◽

Severe Disease ◽

Small Animal ◽

T Cell Responses ◽

Hemorrhagic Fever ◽

Type I ◽

Crimean Congo Hemorrhagic Fever ◽

Cell Responses

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a cause of severe hemorrhagic fever. Its tick reservoir and vector are widely distributed throughout Africa, Southern and Eastern Europe, the Middle East, and Asia. Serological evidence suggests that CCHFV can productively infect a wide variety of species, but only humans develop severe, sometimes fatal disease. The role of the host adaptive immunity in control or contribution to the severe pathology seen in CCHF cases is largely unknown. Studies of adaptive immune responses to CCHFV have been limited due to lack of suitable small animal models. Wild-type mice are resistant to CCHFV infection, and type I interferon-deficient mice typically develop a rapid-onset fatal disease prior to development of adaptive immune responses. We report here a mouse model in which type I interferon-deficient mice infected with a clinical isolate of CCHFV develop a severe inflammatory disease but ultimately recover. Recovery was coincident with development of CCHFV-specific B- and T-cell responses that were sustained for weeks postinfection. We also found that recovery from a primary CCHFV infection could protect against disease following homologous or heterologous reinfection. Together this model enables study of multiple aspects of CCHFV pathogenesis, including convalescence, an important aspect of CCHF disease that existing mouse models have been unsuitable for studying. IMPORTANCE The role of antibody or virus-specific T-cell responses in control of acute Crimean-Congo hemorrhagic fever virus infection is largely unclear. This is a critical gap in our understanding of CCHF, and investigation of convalescence following severe acute CCHF has been limited by the lack of suitable small animal models. We report here a mouse model of CCHF in which infected mice develop severe disease but ultimately recover. Although mice developed an inflammatory immune response along with severe liver and spleen pathology, these mice also developed CCHFV-specific B- and T-cell responses and were protected from reinfection. This model provides a valuable tool to investigate how host immune responses control acute CCHFV infection and how these responses may contribute to the severe disease seen in CCHFV-infected humans in order to develop therapeutic interventions that promote protective immune responses.

Download Full-text

RIG-I Mediates an Antiviral Response to Crimean-Congo Hemorrhagic Fever Virus

Journal of Virology ◽

10.1128/jvi.01643-15 ◽

2015 ◽

Vol 89 (20) ◽

pp. 10219-10229 ◽

Cited By ~ 17

Author(s):

Jessica R. Spengler ◽

Jenish R. Patel ◽

Ayan K. Chakrabarti ◽

Marko Zivcec ◽

Adolfo García-Sastre ◽

...

Keyword(s):

Public Health ◽

Rna Virus ◽

Hemorrhagic Fever ◽

Antiviral Response ◽

Fever Virus ◽

Type I ◽

Immune Recognition ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus ◽

Significant Public Health

ABSTRACTIn the cytoplasm, the retinoic acid-inducible gene I (RIG-I) senses the RNA genomes of several RNA viruses. RIG-I binds to viral RNA, eliciting an antiviral response via the cellular adaptor MAVS. Crimean-Congo hemorrhagic fever virus (CCHFV), a negative-sense RNA virus with a 5′-monophosphorylated genome, is a highly pathogenic zoonotic agent with significant public health implications. We found that, during CCHFV infection, RIG-I mediated a type I interferon (IFN) response via MAVS. Interfering with RIG-I signaling reduced IFN production and IFN-stimulated gene expression and increased viral replication. Immunostimulatory RNA was isolated from CCHFV-infected cells and from virion preparations, and RIG-I coimmunoprecipitation of infected cell lysates isolated immunostimulatory CCHFV RNA. This report serves as the first description of a pattern recognition receptor for CCHFV and highlights a critical signaling pathway in the antiviral response to CCHFV.IMPORTANCECCHFV is a tick-borne virus with a significant public health impact. In order for cells to respond to virus infection, they must recognize the virus as foreign and initiate antiviral signaling. To date, the receptors involved in immune recognition of CCHFV are not known. Here, we investigate and identify RIG-I as a receptor involved in initiating an antiviral response to CCHFV. This receptor initially was not expected to play a role in CCHFV recognition because of characteristics of the viral genome. These findings are important in understanding the antiviral response to CCHFV and support continued investigation into the spectrum of potential viruses recognized by RIG-I.

Download Full-text