Two-component system VraSR senses host defense peptide PMAP-36 to promote Streptococcus suis pathogenicity through regulating accD expression

Streptococcus suis ( S. suis ) is an important zoonotic pathogen that causes severe infections in humans and animals worldwide. Upon infection, the host innate immune system produces host defense peptides (HDPs) to resist S. suis invasion. PMAP-36, a porcine-derived HDP, has been shown to fail to kill S. suis , suggesting that this pathogen has evolved strategies to evade PMAP-36-mediated immune defense. However, the exact mechanism by which S. suis responds to PMAP-36 remains unclear. Here we showed that PMAP-36 significantly enhanced S. suis adhesion, cytotoxicity, and virulence gene expression. The two-component system (TCS) VraSR was essential for PMAP-36 to promote S. suis pathogenicity. We demonstrated that PMAP-36 directly bound to the sensor kinase VraS. Further transcriptomic analysis revealed that VraSR sensed PMAP-36 to regulate fatty acid biosynthesis, in which a key gene accD expression was significantly downregulated in both PMAP-36-treated Δ vraS and Δ vraR mutant strains. Deletion of accD attenuates S. suis in vivo pathogenicity, including reduced bacterial loads, alleviated organ damage, and decreased inflammatory response. Additionally, VraSR-mediated accD expression was critical for S. suis -induced cytotoxicity and inflammatory response, as deletion of vraS or vraR fails to reduce inflammatory cytokines production due to sustained high accD expression. This study reveals VraSR-mediated virulence regulatory mechanism in response to HDP activation, which provides new insight into the development of novel strategies to combat S. suis infection.