NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis
Authors
Pandey, Amit K.Yang, Yibin
Jiang, Zhaozhao
Fortune, Sarah M.
Coulombe, Francois
Behr, Marcel A.
Fitzgerald, Katherine A.
Sassetti, Christopher M.
Kelliher, Michelle A.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Disease and ImmunologyDepartment of Cancer Biology
Department of Molecular Genetics and Microbiology
Document Type
Journal ArticlePublication Date
2009-07-07Keywords
Acetylmuramyl-Alanyl-IsoglutamineAnimals
Bacterial Proteins
Cell Line
Interferon Regulatory Factor-3
Interferon Regulatory Factors
Interferon Type I
Macrophages
Mice
Mice, Inbred C57BL
Mutation
Mycobacterium tuberculosis
Nod2 Signaling Adaptor Protein
Protein-Serine-Threonine Kinases
Receptor-Interacting Protein Serine-Threonine
Kinases
Tuberculosis
Ubiquitin
Cancer Biology
Immunology and Infectious Disease
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
While 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.Source
PLoS Pathog. 2009 Jul;5(7):e1000500. Epub 2009 Jul 3. Link to article on publisher's siteDOI
10.1371/journal.ppat.1000500Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39282PubMed ID
19578435Related Resources
Link to Article in PubMedRights
Copyright: © 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.ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1000500