The host inflammatory response contributes to disease severity in Crimean-Congo hemorrhagic fever virus infected mice

Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. In cell culture, CCHFV is sensed by the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I) molecule and its adaptor molecule mitochondrial antiviral signaling (MAVS) protein. MAVS initiates both type I interferon (IFN-I) and proinflammatory responses. Here, we studied the role MAVS plays in CCHFV infection in mice in both the presence and absence of IFN-I activity. MAVS-deficient mice were not susceptible to CCHFV infection when IFN-I signaling was active and showed no signs of disease. When IFN-I signaling was blocked by antibody, MAVS-deficient mice lost significant weight, but were uniformly protected from lethal disease, whereas all control mice succumbed to infection. Cytokine activity in the infected MAVS-deficient mice was markedly blunted. Subsequent investigation revealed that CCHFV infected mice lacking TNF-alpha receptor signaling (TNFA-R-deficient), but not IL-6 or IL-1 activity, had more limited liver injury and were largely protected from lethal outcomes. Treatment of mice with an anti-TNF-alpha neutralizing antibody also conferred partial protection in a post-virus exposure setting. Additionally, we found that a disease causing, but non-lethal strain of CCHFV produced more blunted inflammatory cytokine responses compared to a lethal strain in mice. Our work reveals that MAVS activation and cytokine production both contribute to CCHFV pathogenesis, potentially identifying new therapeutic targets to treat this disease. Author summary CCHFV causes a spectrum of disease in humans that can range from minimally symptomatic to a catastrophic and lethal infection. Factors dictating why some develop mild illness and others succumb to disease are unclear. Epidemiological studies suggest that the host inflammatory response may be an important factor in mediating different disease outcomes. Here we used a murine model to experimentally demonstrate that indeed the host inflammatory response is an important factor for CCHFV pathogenesis. Genetic disruption of a specific pathogen sensing pathway or an important inflammatory cytokine signaling pathway afforded the host a survival advantage. Additionally, pharmacological targeting of cytokine activity also conferred protection to the infected host. We also found that a strain of CCHFV that does not cause lethal disease in mice, also does not induce as potent of an inflammatory cytokine response as lethal strains, despite similar levels of replication. Our findings provide evidence that indeed the host response is an important component of the CCHFV pathogenic process, thus identifying host targets for pharmaceutical intervention.