Effect of genomic variations in severe fever with thrombocytopenia syndrome virus on the disease lethality

Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne bunyavirus, causes mild-to-moderate infection to critical illness or even death in human patients. The effect of virus variations on virulence and related clinical significance is unclear. We prospectively recruited SFTSV-infected patients in a hotspot region of SFTS endemic in China from 2011 to 2020, sequenced whole genome of SFTSV, and assessed the association of virus genomic variants with clinical data, viremia, and inflammatory response. We identified seven viral clades (I-VII) based on phylogenetic characterization of 805 SFTSV genome sequences. A significantly increased case fatality rate (32.9%) was revealed in one unique clade (IV) that possesses a specific co-mutation pattern, compared to other three common clades (I, 16.7%; II, 13.8%; and III, 11.8%). The phenotype-genotype association (hazard ratios ranged 1.327-2.916) was confirmed by multivariate regression adjusting age, sex, and hospitalization delay. We revealed a pronounced inflammation response featured by more production of CXCL9, IL-10, IL-6, IP-10, M-CSF, and IL-1 beta, in clade IV, which was also related to severe complications. We observed enhanced cytokine expression from clade IV inoculated PBMCs and infected mice. Moreover, the neutralization activity of convalescent serum from patients infected with one specified clade was remarkably reduced to other viral clades. Together, our findings revealed a significant association between one specific viral clade and SFTS fatality, highlighting the need for molecular surveillance for highly lethal strains in endemic regions and unravelled the importance of evaluating cross-clade effect in development of vaccines and therapeutics.