Abstract
Streptococcus suis, a major zoonotic pathogen, employs diverse strategies to enhance virulence, yet the role of host-derived metabolites in its pathogenicity remains underexplored. Here, we reveal a novel mechanism by which S. suis utilizes lysophosphatidylcholine (lysoPC), a host lipid signaling molecule, to enhance its virulence through treC-dependent carbohydrate metabolic reprogramming. Transcriptomic analysis of lysoPC-treated S. suis revealed significant upregulation of carbohydrate metabolism genes, particularly treC, which encodes trehalose-6-phosphate hydrolase (TreC) and drives trehalose biosynthesis by catalyzing the conversion of trehalose-6-phosphate to trehalose, a pathway absent in mammals. In murine infection models, lysoPC-exposed wild-type (WT) S. suis caused more rapid mortality, increased bacterial loads in systemic organs, and enhanced cytotoxicity towards human endothelial cells. Strikingly, these effects were abolished in ΔtreC mutants but restored upon genetic complementation, confirming treC as indispensable for lysoPC-mediated virulence. Notably, transcriptomic analysis revealed that canonical virulence genes remained unaltered, underscoring metabolic adaptation as the primary driver. Histopathological analysis further demonstrated lysoPC-enhanced pulmonary and hepatic damage in a treC-dependent manner. Our findings establish that S. suis exploits environmental lysoPC to rewire central metabolism via treC, bypassing traditional virulence pathways. This metabolic-virulence coupling highlights treC as a therapeutic target to disrupt lysoPC-driven pathogenicity. By bridging host lipid signaling with bacterial metabolic plasticity, this study advances our understanding of niche-specific virulence strategies and offers new avenues for combating S. suis infections.