Host antimicrobial peptide LL-37 inhibits CovS kinase activity and antagonizes CovR-Mediated activation in group A Streptococcus.

The pathogenicity of Group A Streptococcus (GAS) is tightly regulated by the CovRS two-component system; however, the nature of the direct interaction between CovR and CovS, and how host signals modulate this system, remain poorly understood. Using surface plasmon resonance (SPR), we confirmed that CovR binds CovS with high affinity. Functional assays further demonstrated that CovR enhances the activation of CovS. The host-derived antimicrobial peptide LL-37 directly interacts with CovS and inhibits its kinase activity. Moreover, LL-37 antagonizes CovR-mediated activation of CovS in a dose-dependent manner. Together, these in vitro findings elucidate a molecular mechanism by which a host antimicrobial peptide modulates a key bacterial virulence regulator. They provide a mechanistic framework for understanding host-pathogen signaling interplay and highlight the CovR-CovS interface as a potential target for future anti-virulence strategies against GAS.