N6-methyladenosine RNA modification promotes Severe Fever with Thrombocytopenia Syndrome Virus infection

Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), a novel bunyavirus primarily transmitted by Haemaphysalis longicornis, induces severe disease with a high mortality rate. N6-methyladenosine (m6A) is a prevalent internal chemical modification in eukaryotic mRNA that has been reported to regulate viral infection. However, the role of m6A modification during SFTSV infection remains elusive. We here reported that SFTSV RNAs bear m6A modification during infection. Manipulating the expressions or activities of host m6A regulators significantly impacted SFTSV infection. Mechanistically, SFTSV recruited m6A regulators through the nucleoprotein to modulate the m6A modification of viral RNA, eventually resulting in enhanced infection by promoting viral mRNA translation efficiency and/or genome RNA stability. m6A mutations in the S genome diminished virus particle production, while m6A mutations in the G transcript impaired the replication of recombinant vesicular stomatitis virus (rVSV) expressing G protein in vitro and in vivo. Interestingly, m6A modification was evolutionarily conserved and facilitated SFTSV infection in primary tick cells. These findings may open an avenue for the development of m6A-targeted anti-SFTSV vaccines, drugs, and innovative strategies for the prevention and control of tick-borne disease.