Type IV secretion-dependent activation of host MAP kinases induces an increased proinflammatory cytokine response to Legionella pneumophila.
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-kappaB 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.
Shin
Sunny
S
Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.
Case
Christopher L
CL
Archer
Kristina A
KA
Nogueira
Catarina V
CV
Kobayashi
Koichi S
KS
Flavell
Richard A
RA
Roy
Craig R
CR
Zamboni
Dario S
DS
D000818:Animals; D016207:Cytokines / Q000276:immunology*; D004789:Enzyme Activation; D018836:Inflammation Mediators / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D016952:Legionella pneumophila / Q000276:immunology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases