The pore-forming toxin β hemolysin/cytolysin triggers p38 MAPK-dependent IL-10 production in macrophages and inhibits innate immunity

Group 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. © 2012 bebien et al.