Talaromyces marneffei suppresses macrophage inflammation by regulating host alternative splicing

Talaromyces marneffei (T. marneffei) immune escape is essential in the pathogenesis of talaromycosis. It is currently known that T. marneffei achieves immune escape through various strategies. However, the role of cellular alternative splicing (AS) in immune escape remains unclear. Here, we depict the AS landscape in macrophages upon T. marneffei infection via high-throughput RNA sequencing and detect a truncated protein of NCOR2 / SMRT, named NCOR2-013, which is significantly upregulated after T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1 / TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Furthermore, we identify TUT1 as the AS regulator that regulates NCOR2-013 production and promotes T. marneffei immune evasion. Collectively, these findings indicate that T. marneffei escapes macrophage killing through TUT1-mediated alternative splicing of NCOR2 / SMRT, providing insight into the molecular mechanisms of T. marneffei immune evasion and potential targets for talaromycosis therapy.

Automated summary

The study reveals the role of cellular alternative splicing in Talaromyces marneffei immune escape. A truncated protein called NCOR2-013 is upregulated after T. marneffei infection and it inhibits the transcriptional activation of pro-inflammatory cytokines. TUT1 is identified as the AS regulator that promotes T. marneffei immune evasion. These findings provide insights into the molecular mechanisms of T. marneffei immune escape and potential targets for talaromycosis therapy.