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

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.

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

“…STAT1-KO mice infected with the 10,200 strain of CCHFV showed pathologic changes at necropsy similar to those seen in humans (Bente et al, 2010). Gross examination of viscera showed petechial hemorrhages of the serosa and intestinal hyperemia, while microscopic study revealed multiple foci of hepatocellular necrosis and prominent lymphocyte depletion and karyrrhectic debris in the spleen, consistent with lymphocyte apoptosis.…”

“…As noted above, many of these findings are replicated in CCHFVinfected STAT-1 KO mice, which develop elevated serum levels of IL-6, IL-10, IFN-c and TNF-a early in the course of illness (Bente et al, 2010). A loss of lymphocytes through apoptosis, which occurs in Ebola HF through the action of inflammatory mediators, may also occur in CCHF.…”

“…Inhibition of CCHFV replication has been demonstrated in a minigenome system (Bergeron et al, 2010), in virus-infected cells (Huggins, 1989;Watts et al, 1989;Paragas et al, 2004), in newborn mice (Tignor and Hanham, 1993) and in STAT-1 KO mice (Bente et al, 2010). Comparisons of a number of virus strains found that they differed no more than a few-fold in sensitivity to the drug Paragas et al, 2004).…”

“…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).…”

“…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.…”