Pathogenicity and virulence of Crimean-Congo hemorrhagic fever virus: From enzootic maintenance to severe human disease

. The virus is endemic across Africa, the Middle East, Asia, and Europe, shaped by the ecology of ixodid ticks and their wildlife hosts. While infection in most vertebrates is asymptomatic, human disease ranges from mild illness to fulminant hemorrhagic fever with vascular leak, multiorgan failure, coagulopathy, and shock, with case-fatality rates up to 30% and no licensed countermeasures. This review synthesizes current understanding of CCHFV pathogenicity and virulence across its enzootic cycle. We highlight host and viral factors driving infection in ticks, intermediate hosts, and humans, including entry, immune evasion, and mechanisms underlying severe disease. We also identify key knowledge gaps and research priorities to advance understanding of CCHFV pathogenesis and inform strategies to mitigate severe disease.