Show simple item record

dc.contributor.authorPandey, Amit K.
dc.contributor.authorYang, Yibin
dc.contributor.authorJiang, Zhaozhao
dc.contributor.authorFortune, Sarah M.
dc.contributor.authorCoulombe, Francois
dc.contributor.authorBehr, Marcel A.
dc.contributor.authorFitzgerald, Katherine A.
dc.contributor.authorSassetti, Christopher M.
dc.contributor.authorKelliher, Michelle A.
dc.date2022-08-11T08:09:38.000
dc.date.accessioned2022-08-23T16:38:36Z
dc.date.available2022-08-23T16:38:36Z
dc.date.issued2009-07-07
dc.date.submitted2010-01-20
dc.identifier.citationPLoS Pathog. 2009 Jul;5(7):e1000500. Epub 2009 Jul 3. <a href="http://dx.doi.org/10.1371/journal.ppat.1000500">Link to article on publisher's site</a>
dc.identifier.issn1553-7374 (Electronic)
dc.identifier.doi10.1371/journal.ppat.1000500
dc.identifier.pmid19578435
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39282
dc.description.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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=19578435&dopt=Abstract">Link to Article in PubMed</a>
dc.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.
dc.subjectAcetylmuramyl-Alanyl-Isoglutamine
dc.subjectAnimals
dc.subjectBacterial Proteins
dc.subjectCell Line
dc.subjectInterferon Regulatory Factor-3
dc.subjectInterferon Regulatory Factors
dc.subjectInterferon Type I
dc.subjectMacrophages
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMutation
dc.subjectMycobacterium tuberculosis
dc.subjectNod2 Signaling Adaptor Protein
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectReceptor-Interacting Protein Serine-Threonine
dc.subjectKinases
dc.subjectTuberculosis
dc.subjectUbiquitin
dc.subjectCancer Biology
dc.subjectImmunology and Infectious Disease
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleNOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis
dc.typeArticle
dc.source.journaltitlePLoS pathogens
dc.source.volume5
dc.source.issue7
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3081&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2082
dc.identifier.contextkey1115543
refterms.dateFOA2022-08-23T16:38:36Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/2082
dc.contributor.departmentDepartment of Medicine, Division of Infectious Disease and Immunology
dc.contributor.departmentDepartment of Cancer Biology
dc.contributor.departmentDepartment of Molecular Genetics and Microbiology
dc.source.pagese1000500


Files in this item

Thumbnail
Name:
19578435.pdf
Size:
1.276Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record