Extrinsic Ecological Factors and Intrinsic Genetic Features are Associated with Ecological Generalism in Pathogenic Tick-Borne Viruses

Abstract Emerging and re-emerging tick-borne viruses (TBVs) have caused numerous outbreaks recently, yet the factors driving their emergence and pathogenicity in humans remain unclear. A global analysis integrating epidemiological and genomic data of all known pathogenic TBVs revealed that highly pathogenic TBVs (HPTBVs) tend to exhibit ecological generalism. Specifically, HPTBVs infect a broader range of tick species, animal hosts, and ecotypes, which likely enhance their transmission to humans. Bird migration is the primary driver for geographic spread of HPTBVs, while livestock density and TBVs’ diversity they carry determine HPTBVs local persistence. HPTBVs experience stronger positive selection in genes related to host interactions, with specific mutations associated with lineage adaptation. Notably, the positively selected D170N mutation in severe fever with thrombocytopenia syndrome virus revealed an enhanced binding affinity to human receptors, which correlated with increased infectivity. These findings underscore ecological and evolutionary factors facilitating TBV generalization, thereby posing significant public health risks.