Bebien, MagaliMagaliBebienHensler, Mary EMary EHenslerDavanture, SuzelSuzelDavantureLI-CHUNG HSUKarin, MichaelMichaelKarinPark, Jin MoJin MoParkAlexopoulou, LenaLenaAlexopoulouLiu, George YGeorge YLiuNizet, VictorVictorNizetLawrence, TobyTobyLawrence2024-04-262024-04-26201215537366http://www.scopus.com/inward/record.url?eid=2-s2.0-84864606683&partnerID=MN8TOARShttps://scholars.lib.ntu.edu.tw/handle/123456789/642061Group B Streptococcus (GBS) is a leading cause of invasive bacterial infections in human newborns and immune-compromised adults. The pore-forming toxin (PFT) β hemolysin/cytolysin (βh/c) is a major virulence factor for GBS, which is generally attributed to its cytolytic functions. Here we show βh/c has immunomodulatory properties on macrophages at sub-lytic concentrations. βh/c-mediated activation of p38 MAPK drives expression of the anti-inflammatory and immunosuppressive cytokine IL-10, and inhibits both IL-12 and NOS2 expression in GBS-infected macrophages, which are critical factors in host defense. Isogenic mutant bacteria lacking βh/c fail to activate p38-mediated IL-10 production in macrophages and promote increased IL-12 and NOS2 expression. Furthermore, targeted deletion of p38 in macrophages increases resistance to invasive GBS infection in mice, associated with impaired IL-10 induction and increased IL-12 production in vivo. These data suggest p38 MAPK activation by βh/c contributes to evasion of host defense through induction of IL-10 expression and inhibition of macrophage activation, a new mechanism of action for a PFT and a novel anti-inflammatory role for p38 in the pathogenesis of invasive bacterial infection. Our studies suggest p38 MAPK may represent a new therapeutic target to blunt virulence and improve clinical outcome of invasive GBS infection.en[SDGs]SDG3journal article10.1371/journal.ppat.1002812228297682-s2.0-84864606683https://scholars.lib.ntu.edu.tw/handle/123456789/369281