Type IV Secretion-Dependent Activation of Host MAP Kinases Induces an Increased Proinflammatory Cytokine Response to Legionella pneumophila

PLoS Pathogens

Dario S. Zamboni¹  Catarina V. Nogueira¹  Richard A. Flavell²  Craig R. Roy³  Kristina A. Archer⁴  Sunny Shin⁴  Christopher L. Case⁴  Koichi S. Kobayashi⁴ 

[1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America;Instituto de Ciencias Biomedicas Dr. Abel Salazar, Universidade do Porto, Porto, Portugal;Section of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America;Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America

关键词: Legionella pneumophila;    Macrophages;    MAPK signaling cascades;    Cytokines;    Secretion systems;    DNA transcription;    Immune receptor signaling;    Immune response;   

DOI  :  10.1371/journal.ppat.1000220

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The immune system must discriminate between pathogenic and nonpathogenic microbes in order to initiate an appropriate response. Toll-like receptors (TLRs) detect microbial components common to both pathogenic and nonpathogenic bacteria, whereas Nod-like receptors (NLRs) sense microbial components introduced into the host cytosol by the specialized secretion systems or pore-forming toxins of bacterial pathogens. The host signaling pathways that respond to bacterial secretion systems remain poorly understood. Infection with the pathogen Legionella pneumophila, which utilizes a type IV secretion system (T4SS), induced an increased proinflammatory cytokine response compared to avirulent bacteria in which the T4SS was inactivated. This enhanced response involved NF-κB activation by TLR signaling as well as Nod1 and Nod2 detection of type IV secretion. Furthermore, a TLR- and RIP2-independent pathway leading to p38 and SAPK/JNK MAPK activation was found to play an equally important role in the host response to virulent L. pneumophila. Activation of this MAPK pathway was T4SS-dependent and coordinated with TLR signaling to mount a robust proinflammatory cytokine response to virulent L. pneumophila. These findings define a previously uncharacterized host response to bacterial type IV secretion that activates MAPK signaling and demonstrate that coincident detection of multiple bacterial components enables immune discrimination between virulent and avirulent bacteria.

【 授权许可】

CC BY