Dynamic m⁶A profiles reveal the role of YTHDC2-TLR2 signaling axis in Talaromyces marneffei infection

Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N-6-methyladenosine (m(6)A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome-wide transcriptional m(6)A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m(6)A levels and upregulation of the m(6)A reader YTH N-6-methyladenosine RNA binding protein C2 (YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m(6)A-dependence, along with upregulation of TNF-alpha and IL1-beta. Overall, we characterized the m(6)A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m(6)A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.