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

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Department of Microbiology Papers
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legionella pneumophila
MAPK signaling cascades
bacterial pathogens
DNA transcription
immune receptor signaling
immune response
Immunology and Infectious Disease
Pathogenic Microbiology
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Case, Christopher L
Archer, Kristina A
Nogueira, Catarina V
Kobayashi, Koichi S
Flavell, Richard A
Roy, Craig R
Zamboni, Dario S

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.

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PLoS Pathogens
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At the time of publication, author Sunny Shin was affiliated with Yale University School of Medicine. Currently, she is a faculty member at the Perelman School of Medicine at the University of Pennsylvania.
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