Dynamic m⁶ A 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. N⁶ -methyladenosine (m⁶ 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 m⁶ A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m⁶ A levels and upregulation of the m⁶ A reader YTH N⁶ -methyladenosine RNA binding protein C2 (YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m⁶ A-dependence, along with upregulation of TNF-α and IL1-β. Overall, we characterized the m⁶ A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m⁶ A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.