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

by Zhiqiang Chen, Jinyu Zhang, Jun Wang, Hao Tong, Wen Pan, Feng Ma, Qihan Wu, Jianfeng Dai

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.