Side-by-side evaluation of two Crimean-Congo hemorrhagic fever virus isolates in IFNAR^-/- mice

Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a severe hemorrhagic fever in humans, associated with case fatality rates up to 40%. Due to the lack of approved vaccines or specific antiviral treatments, CCHFV is classified as a biosafety level 4 (BSL4) pathogen in most countries and designated a priority pathogen by the World Health Organization. To facilitate the preclinical assessment of medical countermeasures, we have established a murine model using C57BL/6J IFNAR^-/- mice, which lack the IFNα/β receptor, infected with the phylogenetically distinct CCHFV strains Afghanistan09-2990 (Afg09) and Kosovo Hoti (Hoti). Infection with both CCHFV strains in IFNAR^-/- mice resulted in significant weight loss, with Afg09 infection leading to more severe clinical disease. Quantitative analysis of viral RNA revealed widespread viral dissemination across multiple organs. Detection of infectious virus varied by organ and strain. These results independently validate previously reported disease phenotypes while providing new insight into strain-specific differences in CCHFV pathogenesis in IFNAR^-/- mice. Thereby, these CCHFV models represent valuable tools for the evaluation of antiviral therapeutics and vaccine candidates, enabling the investigation of cross-lineage protection against genetically diverse CCHFV isolates.