Inflammation associated with monocyte/macrophage activation and recruitment corresponds with lethal outcome in a mouse model of Crimean-Congo haemorrhagic fever

Authors: SORVILLO, TERESA - Centers For Disease Control And Prevention (CDC) - United States; RITTER, JANA - Centers For Disease Control And Prevention (CDC) - United States; WELCH, STEPHEN - Centers For Disease Control And Prevention (CDC) - United States; COLEMAN-MCCRAY, JOANN - Centers For Disease Control And Prevention (CDC) - United States; DAVIES, KATHERINE - Oak Ridge Institute For Science And Education (ORISE); HAYES, HEATHER - Centers For Disease Control And Prevention (CDC) - United States; PEGAN, SCOTT - Centers For Disease Control And Prevention (CDC) - United States; MONTGOMERY, JOEL - University Of California; SPIROPOULOU, CHRISTINA - Centers For Disease Control And Prevention (CDC) - United States; SPENGLER, JESSICA - Centers For Disease Control And Prevention (CDC) - United States; BERGERON, ERIC - Centers For Disease Control And Prevention (CDC) - United States

Submitted to: Emerging Microbes & Infections
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/6/2025
Publication Date: 11/8/2025
Citation: Sorvillo, T.E., Ritter, J.M., Welch, S.R., Coleman-Mccray, J.D., Davies, K.A., Hayes, H.M., Pegan, S.D., Montgomery, J.M., Spiropoulou, C.F., Spengler, J.R., Bergeron, E. 2025. Inflammation associated with monocyte/macrophage activation and recruitment corresponds with lethal outcome in a mouse model of Crimean-Congo haemorrhagic fever. 13(1). Article 2427782. https://doi.org/10.1080/22221751.2024.2427782.
DOI: https://doi.org/10.1080/22221751.2024.2427782

Interpretive Summary: Crimean-Congo haemorrhagic fever virus (CCHFV) can cause disease in humans, with disease ranging from sub clinical to fatal. However, there is a lack of robust animal models allowing investigation into this variable disease presentation. A recently described mouse model, where an antibody is used to transiently suppress the interferon response, has been shown to induce susceptibility to CCHFV. Here, the effects of route-, immunosupression, sex, age and virus strain on clinical course and outcome were evaluated. It was found that lethality was strain dependent with the IbAr10200 strain causing lethal disease whereas the Turkey04 strain produced transient illness. Fatal outcomes were marked by elevated inflammation. These findings suggest early macrophage-drive inflammation as a potential factor in severe disease and suggest modulating inflammation as a potential therapeutic target.

Technical Abstract: Crimean-Congo haemorrhagic fever virus (CCHFV) causes human disease ranging from subclinical to a fatal haemorrhagic syndrome. Determinants of CCHF pathogenesis are largely unknown and animal models that recapitulate human disease are limited. A recently described mouse model uses a monoclonal antibody (mAb 5A3) targeting the interferon (IFN) alpha/beta receptor to suppress type I IFN responses, making animals transiently susceptible to infection. To advance utility of this model, we investigated effects of challenge route, timing of 5A3 delivery, mouse sex and age, and virus strain on clinical course and outcome. C57BL/6J mice received mAb 5A3 -1, 0, or -1/+1 days post-infection (dpi). Subsets were challenged with CCHFV strain Turkey04 or IbAr10200 subcutaneously or intraperitoneally, and serially euthanized 3- and 7-dpi, when meeting euthanasia criteria or at study completion (14 dpi). CCHFV-IbAr10200-infected mice almost uniformly succumbed to infection, whereas CCHFV-Turkey04-infected mice transiently lost weight but survived. These results were consistent regardless of mAb timing or route of challenge. Viral replication and dissemination were comparable between the two strains at 3 dpi. However, in the plasma and livers of non-survivors, expression of proinflammatory cytokines/chemokines that correspond with macrophage activation and recruitment were significantly elevated. Lethal disease was also associated with elevated levels of macrophage activation marker CD163 in plasma. Further, mouse macrophages were more permissive to IbAr1200 infection in vitro, suggesting tropism for these cells may influence pathogenesis. Our data suggest that early inflammation may be a critical determinant of CCHF outcome and therapeutics to control inflammation may be worthwhile targets for future investigation.