title: 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.
authors: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France.
authors: Magali
authors: M
authors: Bebien
authors: Mary E
authors: ME
authors: Hensler
authors: Suzel
authors: S
authors: Davanture
authors: Li-Chung
authors: LC
authors: Hsu
authors: Michael
authors: M
authors: Karin
authors: Jin Mo
authors: JM
authors: Park
authors: Lena
authors: L
authors: Alexopoulou
authors: George Y
authors: GY
authors: Liu
authors: Victor
authors: V
authors: Nizet
authors: Toby
authors: T
authors: Lawrence
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D006460:Hemolysin Proteins / Q000378:metabolism*; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D013290:Streptococcal Infections / Q000276:immunology* / Q000382:microbiology; D013292:Streptococcus agalactiae / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D006460:Hemolysin Proteins; D016753:Interleukin-10; C071495:streptococcal group B hemolysin; D018664:Interleukin-12; D019001:Nitric Oxide Synthase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases