Induction of cyclophilin A by influenza A virus infection facilitates group A Streptococcus coinfection

During influenza A epidemics, bacterial coinfection is a major cause of increased morbidity and mortality. However, the roles of host factors in regulating influenza A virus (IAV)-triggered bacterial coinfection remain elusive. Cyclophilin A (CypA) is an important regulator of infection and immunity. Here, we show that IAV-induced CypA expression facilitates group A Streptococcus (GAS) coinfection both in vitro and in vivo. Upon IAV infection, CypA interacts with focal adhesion kinase (FAK) and inhibited E3 ligase cCbl-mediated, K48-linked ubiquitination of FAK, which positively regulates integrin alpha 5 expression and actin rearrangement via the FAK/Akt signaling pathway to facilitate GAS colonization and invasion. Notably, CypA deficiency or inhibition by cyclosporine A significantly inhibits IAV-triggered GAS coinfection in mice. Collectively, these findings reveal that CypA is critical for GAS infection, and induction of CypA expression is another way for IAV to promote bacterial coinfection, suggesting that CypA is a promising therapeutic target for the secondary bacterial infection.

Automated summary

During influenza A epidemics, bacterial coinfection is a major cause of increased morbidity and mortality. Cyclophilin A (CypA) is shown to play a critical role in promoting group A Streptococcus (GAS) coinfection by regulating the FAK/Akt signaling pathway, revealing a potential therapeutic target for preventing secondary bacterial infections during influenza A outbreaks.