Shin, SunnyCase, Christopher L.Archer, Kristina A.Nogueira, Catarina V.Kobayashi, Koichi S.Flavell, Richard A.Roy, Craig R.Zamboni, Dario S.2011-04-262008Shin, Sunny, Christopher L. Case, Kristina A. Archer, Catarina V. Nogueira, Koichi S. Kobayashi, Richard A. Flavell, Craig R. Roy, and Dario S. Zamboni. 2008. Type IV secretion-dependent activation of host MAP kinases induces an increased proinflammatory cytokine response to Legionella pneumophila. PLoS Pathogens 4(11): e1000220.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:4875872The 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.en-USmicrobiologycellular microbiology and pathogenesisimmunity to infectionsinnate immunityJournal Article2011-04-2610.1371/journal.ppat.1000220