Streptococcus suis serotype 2 collagenase-like protease promotes meningitis by increasing blood-brain barrier permeability1

serotype 2 (SS2) is an emerging zoonotic pathogen that causes meningitis in humans and pigs. It not only brings huge economic losses to the pig industry but also seriously threatens public health security. However, the mechanisms by which SS2 enters the brain and induces meningitis is not fully understood. Here, we investigated the role and mechanism of the SS2 collagenase-like protease (Clp) in promoting the passage of the bacterium across the blood-brain barrier (BBB). We found that SS2 Clp enhanced virulence and tissue colonization, and promoted the destruction of the BBB in mice. Compared with wild-type SS2, the ability of a Δ mutant to cross human brain microvascular endothelial (hCMEC/D3) cell monolayers decreased, whereas the addition of recombinant protein rClp increased permeability. rClp also significantly promoted the adhesion of SS2 to hCMEC/D3, inhibited the expression of intercellular tight junction proteins ZO-1, Occludin, and Claudin-5 independent of its enzyme activity, and induced hCMEC/D3 apoptosis through the cell receptor ligand apoptosis and mitochondrial apoptosis pathways partly dependent on its enzyme activity, resulting in BBB destruction and increased permeability. Moreover, Clp increased macrophage (F4/80+), monocytes (F4/80-Ly6C+), and neutrophils (Ly6G+) infiltration into the brain after SS2 infection. Thus, SS2 Clp is required for the passage of the bacterium across the BBB, and the results, provide a theoretical basis for better prevention and treatment of SS2-induced meningitis.