Extracellular Vesicles from Streptococcus suis Promote Bacterial Pathogenicity by Disrupting Macrophage Metabolism

<i>Streptococcus suis</i> (<i>S. suis</i>) is an important zoonotic pathogen that causes severe disease in both humans and pigs, leading to substantial economic losses in the swine industry. Extracellular vesicles (EVs), as critical mediators of host-pathogen interactions, play key roles in bacterial virulence and disease progression. This study aimed to investigate the biological properties of <i>S. suis</i> EVs and elucidate their role in the bacterium's pathogenesis. We isolated and characterized <i>S. suis</i> EVs, which were found to contain diverse protein molecules. EVs were efficiently internalized by mammalian cells, and concentrations below 50 μg/mL did not affect cell viability. Following uptake, EVs suppressed the production of key pro-inflammatory cytokines (<i>TNF-α</i>, <i>IL-1β</i>, and <i>IL-8</i>) by modulating macrophage metabolism. They also downregulated the expression of major histocompatibility complex class II (MHC-II) and adhesion molecules (<i>VCAM-1</i> and <i>ICAM-1</i>) during subsequent infections, potentially impairing macrophage-mediated clearance. In addition, EVs served as vectors for efficient cargo delivery and facilitated <i>S. suis</i> adhesion to and invasion of endothelial cells. In infection models, EVs markedly enhanced lethality in <i>Galleria mellonella</i> larvae and promoted tissue colonization in murine models. These findings suggest that <i>S. suis</i> EVs are key mediators of host-pathogen interactions, contributing to colonization and disease pathogenesis. Moreover, they offer novel insights and potential strategies for the prevention and control of <i>S. suis</i> infections.