The Pore-Forming Toxin β hemolysin/cytolysin Triggers p38 MAPK-Dependent IL-10 Production in Macrophages and Inhibits Innate Immunity

Abstract

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.

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

“…A recent study found that sublytic concentrations of group B streptococcus (GBS) ␤-hemolysin/cytolysin (␤-h/c) inhibited IL-12 and nitric oxide synthase 2 (NOS2) expression in mouse primary macrophages (361). ␤-h/c also activated JNK and p38 MAPKs, independently of TLR2, TLR4, the NLR protein NOD2, and the inflammasome.…”

“…In many cases, PFTs impair immune defenses, and this is accomplished through several different mechanisms. These include allowing bacteria to physically hide from the immune system and survive phagocytosis (e.g., L. monocytogenes LLO [424,425], M. tuberculosis ESAT-6 [122], GBS ␤-h/c [361], S. aureus alpha-toxin [435], and C. perfringens PFO [92]), preventing the activation of immune pathways (e.g., complement activation by S. pneumoniae PLY [181] or inhibition of the IgG and IgM response by LLO during L. monocytogenes infection [383]), and preventing the actions of antimicrobial compounds (178,447).…”

PSM Peptides of Staphylococcus aureus Activate the p38–CREB Pathway in Dendritic Cells, Thereby Modulating Cytokine Production and T Cell Priming

“…Our data indicate a direct interaction of PSMa peptides with p38, thereby enhancing its phosphorylation and via CREB activation (20) eventually leading to high IL-10 production in DCs upon TLR2 ligand stimulation. This conclusion is supported by Bebien et al (18) showing that the virulence factor b hemolysin/cytolysin of group B streptococcus induces IL-10 secretion via p38 MAPK activation. PFTs activate MAPK signaling pathways in different eukaryotic cells; whether this is beneficial or detrimental for the pathogen is species dependent (29)(30)(31)(32)(33)(34)(35)(36).…”

“…The virulence factor b hemolysin/cytolysin of group B streptococcus was shown to induce IL-10 secretion in macrophages by activating p38 MAPK (18). Furthermore, TLR2 stimulation of DCs leads to phosphorylation of ERK1/2, which induces IL-10 production (19) (Fig.…”

The NOD2 receptor modulates the cytokine response but does not alter the clinical outcome of Group B Streptococcus-infected mice

“…Recently, Costa et al [32] reported that activation of the inflammasome, an inflammatory signaling complex, by GBS is implicated in host defense against this pathogen. On the other hand, in vitro studies performed to date were unable to prove a clear role of NOD in GBS interactions with macrophages [29,30] .…”