Lethal Sudan virus infection in IFNAR -/- mice reveals hallmarks of a cytokine storm

Abstract Sudan virus (SUDV) is a member of the family Filoviridae, which comprises highly pathogenic viruses associated with unusually high case fatality rates. The development of medical countermeasures against filoviruses, including antivirals, vaccines, and therapeutic antibodies, requires preclinical evaluation in suitable animal models. C57BL/6J IFNAR-/- mice, which lack the type I interferon (IFN-α/β) receptor, have been reported to be susceptible to filovirus infections, although their impaired innate immune response may represent a potential limitation of the model. Here, we show that IFNAR-/- mice constitute a suitable model for SUDV infection. Following infection, animals developed a clear clinical disease characterized by significant weight loss and pronounced changes in behaviour and appearance. Mice reached the predefined clinical endpoint 3–5 days post infection. Post mortem analysis of terminal samples revealed high viral loads and viral genome copies in all tested organs as well as in serum, indicating widespread systemic dissemination. Importantly, infection was associated with a marked increase in several key chemokines and cytokines linked to systemic inflammation, consistent with the development of a cytokine storm–like response. Together, these findings demonstrate that SUDV infection in IFNAR-/- mice induces systemic viral dissemination and a pronounced inflammatory response, supporting the suitability of this model for investigating filovirus pathogenesis and infection-associated immune dysregulation. Competing Interest Statement The authors have declared no competing interest. Abbreviations - BSL-4 - biosafety level-4; - Dpi - days post infection; - EBOV - Ebola virus; - ELISA - enzyme-linked immunosorbent assay; - G-CSF - granulocyte-colony stimulating factor; - GM-CSF - granulocyte-macrophage colony-stimulating factor; - IFN-γ - interferon gamma; - IFNAR-/- - interferon receptor alpha/beta knockout mice; - IL - interleukin; - i.p. - intraperitoneally; - KC - keratinocyte-derived chemokine; - LLOQ - lower limit of quantification; - LOD - limit of detection; - MARV - Marburg virus; - MCP-1 - monocyte chemotactic protein-1; - MIP - macrophage inflammatory protein; - PFU - plaque forming units; - RANTES - Regulated upon Activation, Normal T cell Expressed and Secreted; - RESTV - Reston virus; - SUDV - Sudan virus; - TNF-α - tumor necrosis factor alpha.