Non-neutralizing antibody responses control acute Crimean-Congo hemorrhagic fever virus infection in naïve mice

Crimean-Congo hemorrhagic fever virus (CCHFV) is the cause of a sometimes-severe viral hemorrhagic fever, CCHF. Severe cases of CCHF often have little-to-no CCHFV-specific antibody responses prior to death. However, it is unclear if the failure to mount an antibody response is the cause of a poor outcome or a correlate of a failed host response. Here, we used a mouse-adapted strain of CCHFV (MA-CCHFV) to investigate the requirement of humoral immunity in control of acute CCHFV infection in immunocompetent mice. We found that mice infected with MA-CCHFV develop a rapid non-neutralizing antibody response, consistent with humans infected with CCHFV. Further, we found that the absence of humoral immunity in male but not female mice resulted in near-uniform mortality. Lastly, we determined that complement but not activating Fc-receptors nor the cytoplasmic Fc-receptor tripartite motif containing protein 21 contributed to antibody-mediated control of MA-CCHFV infection. Together, our findings identify rapid humoral immune responses as a critical component of the host response to acute CCHFV infection in naive hosts.IMPORTANCECrimean-Congo hemorrhagic fever virus (CCHFV) is the cause of a serious viral hemorrhagic fever in humans. Severe disease and poor outcomes are correlated with little-to-no CCHFV-specific antibody. However, it is unknown if the lack of CCHFV-specific antibody is a direct cause or merely a correlate of a poor outcome. Here, we investigated the contribution of humoral immunity in control of acute CCHFV infection in naive immunocompetent mice. We found that mice develop a rapid, non-neutralizing antibody response that is crucial for control of the acute infection. Further, we found that loss of complement but not activating Fc receptors or the cytoplasmic Fc receptor TRIM21 worsened disease. Together, our findings suggest that lack of CCHFV-specific antibody responses may directly contribute to poor outcomes in CCHFV-infected humans.