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.
Highlights
The pore-forming toxin (PFT) b hemolysin/cytolysin is a major virulence factor for Group B streptococcus (GBS), which is generally attributed to its cytolytic functions that aid invasion and avoid phagocytic killing [1]
Our studies show b hemolysin/cytolysin from Group B Streptococcus (GBS), inhibits the activation of macrophages and the innate immune response to GBS
We show that bh/c triggers activation of mitogen activated protein kinase (MAPK) in GBS-infected macrophages leading to expression of the anti-inflammatory cytokine interleukin (IL)-10 and the suppression of genes required for effective anti-bacterial immunity
Summary
The pore-forming toxin (PFT) b hemolysin/cytolysin (bh/c) is a major virulence factor for Group B streptococcus (GBS), which is generally attributed to its cytolytic functions that aid invasion and avoid phagocytic killing [1]. The molecular basis of the host response to bh/c, is critical to understanding the pathogenesis of invasive infections caused by GBS, and may reveal new therapeutic targets to blunt virulence and improve clinical outcome. Macrophages are critical effectors of host defense against bacterial infection [5]; as professional phagocytes, they eliminate bacteria through the coordinate activation of phagocyte oxidase (Nox2), inducible nitric oxide synthase (NOS2), antimicrobial peptides and proteases. Macrophages are important effectors for the resolution of inflammation, through the production of anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)b, which is critical to limit damage to host tissues [6]. Pathogens may hijack anti-inflammatory signaling pathways in macrophages that dampen the immune response and resolve inflammation
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