METTL3 Plays Regulatory Roles in Acute Pneumonia during Staphylococcus aureus Infection

Pneumonia caused by Staphylococcus aureus infection has consistently been a significant cause of morbidity and mortality worldwide. Extensive research to date indicates that N6-methyladenosine (m6A) modification plays a crucial role in the development and progression of various diseases. However, it remains unknown whether the m6A modification affects the progression of bacterial pneumonia. To explore this question, we assessed the levels of m6A as well as the expression of methyltransferases (METTL3 and METTL14), demethylase fat mass and obesity-related protein (FTO), and methylation reader proteins YTHDF1 and YTHDF2 in mice and MH-S cells during S. aureus infection. The levels of m6A and METTL3 were significantly upregulated in S. aureus-infected mice and MH-S cells. siMETTL3 knockdown resulted in more severe bacterial colonization, lung damage, increased inflammatory cytokines (IL-6, IL-1 beta, TNF-alpha), and mortality rates in mice as well as MH-S cells following the bacterial infection. Regulation of lung inflammation levels by METTL3 was associated with the activation of the MAPK/NF-kappa B/JAK2-STAT3 signaling pathway. Moreover, siMETTL3 mice exhibited an increased release of superoxides and exacerbated oxidative stress in the lungs following S. aureus infection, which was correlated with impaired mitochondrial autophagy mediated by the Pink1/Parkin pathway. Our findings provide previously unrecognized evidence of the protective role of METTL3 in S. aureus-induced acute pneumonia, indicating a potential therapeutic target for S. aureus infections.