Two-Component Signal Transduction System VraSR Contributes to Neuroinflammation in Streptococcus Suis Meningitis

Abstract Background: Streptococcus suis (S. suis) is an important zoonotic pathogen that can cause high morbidity and mortality in both humans and swine. As the most important life-threatening infection of the central nervous system (CNS), meningitis is an important symptom of S. suis infection. The VraSR is a critical two-component signal transduction system that affects S. suis ability to resist against host innate immune system and promotes the ability of S. suis to adhere to hBMEC. Whether and how VraSR contributes to the development of S. suis meningitis are currently unknown.Methods: The in vivo colonization, in vivo BBB permeability, histopathological examination and immunohistochemistry were applied to compare and characterize the degree of destruction of brain tissue in response to wild type SC19 and mutant ΔvraSR. Western blotting and real-time PCR were combined to identify the breakdown of tight junction proteins (TJ proteins). The secretion of proinflammatory cytokines and chemokines in the serum were detected on a BD FACSVerse flow cytometer.Results: We found an important role of VraSR regulatory system in S. suis SC19-induced meningitis. A mouse infection model demonstrated that ΔvraSR had significantly attenuated inflammatory lesions in the brain tissues compared with wild-type S. suis. In vitro, we characterized that SC19 could increase the blood-brain barrier (BBB) permeability through downregulating the TJ proteins compared with mutant ΔvraSR. Moreover, we found significant generation of proinflammatory cytokines and chemokines in the serum including IL-6, TNF-α, MCP-1, and IL-12p70 compared with ΔvraSR infected mice.Conclusions: For the first time, our work investigated the VraSR regulatory system of S. suis played an important role in streptococcal meningitis and revealed VraSR to be an important contributor to the disruption of TJ proteins. Characterization of these BBB disruption will facilitate further study of meningitis mechanisms in humans, thereby offering the development of novel preventative and therapeutic strategies against infection with S. suis.