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

PLoS Pathogens

Suzel Davanture¹  Lena Alexopoulou¹  Michael Karin²  Magali Bebien²  Toby Lawrence³  Li-Chung Hsu⁴  Victor Nizet⁵  George Y. Liu⁵  Mary E. Hensler⁶  Jin Mo Park⁶ 

[1] Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France;Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France;Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America;Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, School of Medicine, La Jolla, California, United States of America;Department of Pharmacology, University of California San Diego, School of Medicine, La Jolla, California, United States of America;Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France

关键词: Macrophages;    MAPK signaling cascades;    Mouse models;    Protein extraction;    Cytokines;    Immune receptor signaling;    Toxins;    Bacterial diseases;   

DOI  :  10.1371/journal.ppat.1002812

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY