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 ΔvraS and ΔvraR 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.