Blocking Extracellular Cyclophilin A-Mediated Adhesion Protects Against Bacterial Infection

Bacterial pneumonia remains a leading cause of mortality and morbidity worldwide and is primarily managed through antibiotic therapy. However, the increasing threat of antimicrobial resistance underscores the urgent need for alternative strategies. In this study, we identify extracellular cyclophilin A (eCypA) as a key host factor that promotes the adherence of bacteria such as group A Streptococcus (GAS) and Streptococcus pneumoniae (S. P.). Using single-nucleus RNA sequencing of mouse lung tissue, we demonstrate that eCypA upregulates the expression of integrin/extracellular matrix adhesion receptors, including integrin α5, fibronectin, and mucin, an effect largely mediated by enhancing the transforming growth factor-β (TGF-β) signaling. Mechanistically, eCypA interacts with TGF-β receptor II, acting as a coactivator to increase its binding to TGF-β1 and amplify downstream signaling. Notably, administration of an anti-CypA monoclonal antibody yields both prophylactic and therapeutic effects against GAS-induced lung damage in mice by reducing bacterial adhesion and suppressing proinflammatory cytokine production. Collectively, these findings identify eCypA as a critical regulator of infection exploited by diverse bacteria that rely on integrin/extracellular matrix for adherence, highlighting eCypA as a promising target for host-directed therapies designed to mitigate bacterial attachment and subsequent inflammation.