NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis
AuthorsPandey, Amit K.
Fortune, Sarah M.
Behr, Marcel A.
Fitzgerald, Katherine A.
Sassetti, Christopher M.
Kelliher, Michelle A.
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Disease and Immunology
Department of Cancer Biology
Department of Molecular Genetics and Microbiology
Interferon Regulatory Factor-3
Interferon Regulatory Factors
Interferon Type I
Mice, Inbred C57BL
Nod2 Signaling Adaptor Protein
Receptor-Interacting Protein Serine-Threonine
Immunology and Infectious Disease
Medicine and Health Sciences
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AbstractWhile the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNalpha and IFNbeta, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds to bacterial peptidoglycan, and this event requires membrane damage that is actively inflicted by the bacterium. Unexpectedly, this recognition triggers the expression of type I interferons in a Tbk1- and Irf5-dependent manner. This response is only partially impaired by the loss of Irf3 and therefore, differs fundamentally from those stimulated by bacterial DNA, which depend entirely on this transcription factor. This difference appears to result from the unusual peptidoglycan produced by mycobacteria, which we show is a uniquely potent agonist of the Nod2/Rip2/Irf5 pathway. Thus, the Nod2 system is specialized to recognize bacteria that actively perturb host membranes and is remarkably sensitive to mycobacteria, perhaps reflecting the strong evolutionary pressure exerted by these pathogens on the mammalian immune system.
SourcePLoS Pathog. 2009 Jul;5(7):e1000500. Epub 2009 Jul 3. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/39282
Related ResourcesLink to Article in PubMed
RightsCopyright: © 2009 Pandey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.