Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice

Bereczky, Sándor; Lindegren, Gunnel; Karlberg, Helen; Åkerström, Sara; Klingström, Jonas; Mirazimi, Alì

doi:10.1099/vir.0.019034-0

Cited by 138 publications

(152 citation statements)

References 26 publications

(15 reference statements)

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“…tion with a similar GMD, providing supporting evidence that the IFN response is crucial for disease manifestation (5). In this study, high viral replication in CCHFV-infected STAT129 mice was present despite the high plasma levels of IFN-␣ and IFN-␤, indicating that IFN is produced but unable to induce an IFN-mediated antiviral state due to the STAT1 knockout.…”

Section: Vol 84 2010 New Animal Model For Crimean-congo Hemorrhagicmentioning

confidence: 48%

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

Bente

Alimonti

Shieh

et al. 2010

J Virol

208

242

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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.

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Section: Vol 84 2010 New Animal Model For Crimean-congo Hemorrhagicmentioning

confidence: 48%

“…Moreover, the results of in vitro studies have shown that the IFN response plays a crucial role in controlling CCHFV replication, and a recent study demonstrates that IFN receptor knockout (KO) mice are highly susceptible to CCHFV infection (3)(4)(5).…”

mentioning

confidence: 99%

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

Bente

Alimonti

Shieh

et al. 2010

J Virol

208

242

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“…Two recent studies using knockout (KO) mice lacking the cell-surface IFN-a,b receptor (Bereczky et al, 2010) or the intracellular signal transducer and activator of transcription (STAT)-1 protein (Bente et al, 2010) have shown the importance of the type I IFN response in controlling disease manifestations. IFN receptor-KO mice develop a rapidly progressive disease, with high tissue viral RNA levels and hepatomegaly.…”

Section: Laboratory Animal Models Of Cchfmentioning

confidence: 99%

“…However, the fact that IFN-KO mice are susceptible to lethal infection indicates the critical role of this antiviral mechanism (Bente et al, 2010;Bereczky et al, 2010). Nitric oxide (NO), a mediator of innate responses, also suppresses CCHFV replication (Simon et al, 2006).…”

Section: Pathogenesis Of Cchfmentioning

confidence: 99%

Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity

et al. 2013

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Bente, Dennis A.; Forrester, Naomi L.; Watts, Douglas M.; McAuley, Alexander J.; Whitehouse, Chris A.; and Bray, Mike, "CrimeanCongo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity" (2013 b s t r a c tCrimean-Congo hemorrhagic fever (CCHF) is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area, from western China to the Middle East and southeastern Europe and throughout most of Africa. CCHFV is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, which do not show signs of illness. The virus circulates in a number of tick genera, but Hyalomma ticks are the principal source of human infection, probably because both immature and adult forms actively seek hosts for the blood meals required at each stage of maturation. CCHF occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock and medical personnel through contact with the body fluids of infected patients. CCHFV is the most genetically diverse of the arboviruses, with nucleotide sequence differences among isolates ranging from 20% for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area, while closely related viruses have been isolated in far distant regions, suggesting that widespread dispersion of CCHFV has occurred at times in the past, possibly by ticks carried on migratory birds or through the international livestock trade. Reassortment among genome segments during co-infection of ticks or vertebrates appears to have played an important role in generating diversity, and represents a potential future source of novel viruses. In this article, we first review current knowledge of CCHFV, summarizing its molecular biology, maintenance and transmission, epidemiology and geographic range. We also include an extensive discussion of CCHFV genetic diversity, including maps of the range of the virus with superimposed phylogenetic trees. We then review the features of CCHF, including the clinical syndrome, diagnosis, treatment, pathogenesis, vaccine development and laboratory animal models of CCHF. The paper ends with a discussion of the possible future geographic range of the virus. For the benefit of researchers, we include a Supplementary Table listing all published reports of CCHF cases and outbreaks in the English-language literature, plus some principal articles in other languages, with total case numbers, case fatality rates and all CCHFV strains on GenBank.

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“…It has been detected in at least 31 species of ticks in the Ixodidae and Argasidae families [10]. A common pathogenic feature of CCHFV is its ability to disable host immune response [11]. The main pathological mechanism is believed to be vascular endothelial damage and the main target is thought to be the reticuloendothelial system [12].…”

Section: Introductionmentioning

confidence: 99%

Molecular and Serological Detection of Crimean-Congo Hemorrhagic Fever Virus in Sulaimani Province, Iraq

Aziz¹,

Ali²,

Jaff³

2016

JBM

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Background: Crimean-Congo hemorrhagic fever virus (CCHFV) is a member of the Nairovirus genus in the Bunyaviridae family and is transmitted by ticks of the Hyalomma genus. It causes severe disease in humans with mortality rates between 3% and 30%. The first case in Iraq was reported in 1979; immediately thereafter, 10 cases were reported, resulting in seven deaths. Several cases were also reported in 1980 in Halabja city in Iraq's Sulaimani province. Methods: Blood samples were collected from two study populations, human and cattle, including butchers working at a slaughterhouse. Ticks were also collected for virus detection from three villages in the Sharazoor district of Sulaimani province. Results: Results of the Reverse Transcription-Polymerase Chain Reaction (RT-PCR) were negative for all human and cattle sera. The tissue prepared from ticks also was negative for CCHFV. An Enzyme-Linked Immunosorbent Assay (ELISA) technique showed that 30 (46.87%) of 64 human sera were positive for the anti-CCHFV IgG antibody. Conclusion: Results show that symptomatic Crimean-Congo hemorrhagic fever (CCHF) is an uncommon disease in the Sulaimani province of Iraq and no clinical cases is reported, due to the eradication of ticks implemented by veterinary authorities. However, other preventive approaches and strategies should be implemented and monitored regularly by local authorities.

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Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice

Cited by 138 publications

References 26 publications

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

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

Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity

Molecular and Serological Detection of Crimean-Congo Hemorrhagic Fever Virus in Sulaimani Province, Iraq

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