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Binding of Fibronectin to SsPepO Facilitates the Development of Streptococcus suis Meningitis. Background: SsPepO is an important virulence in Streptococcus suis. Methods: In this study, we showed that SsPepO contributes to the human fibronectin-mediated adherence ability of S. suis to human brain microvascular endothelial cells. Results: The addition of an antifibronectin antibody or an arginine-glycine-aspartic acid peptide that blocks fibronectin binding to integrins significantly reduced adherence of the wild-type but not the SspepO mutant strain, indicating the importance of the SsPepO-fibronectin-integrin interaction for S. suis cellular adherence. Conclusions: By analyzing Evans blue extravasation in vivo, we showed that the interaction between SsPepO and human fibronectin significantly increased permeability of the blood-brain barrier. Furthermore, the SspepO mutant caused lower bacterial loads in the brain than wild-type S. suis in models of meningitis. These data demonstrate that SsPepO is a fibronectin-binding protein, which plays a contributing role in the development of S. suis meningitis.