{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T16:24:57Z","timestamp":1793377497703,"version":"4.5.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2008,11,1]],"date-time":"2008-11-01T00:00:00Z","timestamp":1225497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>NOD2\/CARD15 mediates innate immune responses to mycobacterial infection. However, its role in the regulation of adaptive immunity has remained unknown. In this study, we examined host defense, T cell responses, and tissue pathology in two models of pulmonary mycobacterial infection, using wild-type and Nod2-deficient mice. During the early phase of aerosol infection with Mycobacterium tuberculosis, Nod2\u2212\/\u2212 mice had similar bacterial counts but reduced inflammatory response on histopathology at 4 and 8 wk postchallenge compared with wild-type animals. These findings were confirmed upon intratracheal infection of mice with attenuated Mycobacterium bovis bacillus Calmette-Gu\u00e9rin. Analysis of the lungs 4 wk after bacillus Calmette-Gu\u00e9rin infection demonstrated that Nod2\u2212\/\u2212 mice had decreased production of type 1 cytokines and reduced recruitment of CD8+ and CD4+ T cells. Ag-specific T cell responses in both the spleens and thoracic lymph nodes were diminished in Nod2\u2212\/\u2212 mice, indicating impaired adaptive antimycobacterial immunity. The immune regulatory role of NOD2 was not restricted to the lung since Nod2 disruption also led to reduced type 1 T cell activation following i.m. bacillus Calmette-Gu\u00e9rin infection. To determine the importance of diminished innate and adaptive immunity, we measured bacterial burden 6 mo after aerosol infection with M. tuberculosis and followed a second infected group for assessment of survival. Nod2\u2212\/\u2212 mice had a higher bacterial burden in the lungs 6 mo after infection and succumbed sooner than did wild-type controls. Taken together, these data indicate that NOD2 mediates resistance to mycobacterial infection via both innate and adaptive immunity.<\/jats:p>","DOI":"10.4049\/jimmunol.181.10.7157","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:00:36Z","timestamp":1397847636000},"page":"7157-7165","source":"Crossref","is-referenced-by-count":187,"title":["NOD2-Deficient Mice Have Impaired Resistance to\n                    <i>Mycobacterium tuberculosis<\/i>\n                    Infection through Defective Innate and Adaptive Immunity"],"prefix":"10.1093","volume":"181","author":[{"given":"Maziar","family":"Divangahi","sequence":"first","affiliation":[{"name":"Department of Cancer Immunology and AIDS. Department of Medicine, McGill University Health Centre , Montreal,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Mostowy","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and AIDS. Department of Medicine, McGill University Health Centre , Montreal,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Coulombe","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and AIDS. Department of Medicine, McGill University Health Centre , Montreal,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kozak","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and AIDS. Department of Medicine, McGill University Health Centre , Montreal,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lo\u00efc","family":"Guillot","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and AIDS. Department of Medicine, McGill University Health Centre , Montreal,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Veyrier","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and AIDS. Department of Medicine, McGill University Health Centre , Montreal,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi S.","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute and Harvard Medical School , Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Flavell","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine , New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Gros","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, McGill University , Montreal,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel A.","family":"Behr","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and AIDS. Department of Medicine, McGill University Health Centre , Montreal,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,11,15]]},"reference":[{"key":"2026012807071786200_R1","first-page":"39","article-title":"Who puts the tubercle in tuberculosis?","volume-title":"Nat. Rev. Microbiol.","year":"2007"},{"key":"2026012807071786200_R2","first-page":"169","article-title":"Mycobacterium tuberculosis and its ability to resist immunity","volume-title":"Novartis Found. Symp.","year":"2007"},{"key":"2026012807071786200_R3","first-page":"3480","article-title":"Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012807071786200_R4","first-page":"327","article-title":"Mycobacterial infection in TLR2 and TLR6 knockout mice","volume-title":"Microbiol. Immunol.","year":"2003"},{"key":"2026012807071786200_R5","first-page":"1715","article-title":"TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012807071786200_R6","first-page":"3155","article-title":"Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012807071786200_R7","first-page":"367","article-title":"Toll-like receptor 4 plays no role in susceptibility of mice to Mycobacterium tuberculosis infection","volume-title":"Tuberculosis","year":"2003"},{"key":"2026012807071786200_R8","first-page":"2400","article-title":"MyD88-deficient mice display a profound loss in resistance to Mycobacterium tuberculosis associated with partially impaired Th1 cytokine and nitric oxide synthase 2 expression","volume-title":"Infect. Immun.","year":"2004"},{"key":"2026012807071786200_R9","first-page":"1790","article-title":"Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88","volume-title":"J. Clin. Invest.","year":"2004"},{"key":"2026012807071786200_R10","first-page":"680","article-title":"Containment of aerogenic Mycobacterium tuberculosis infection in mice does not require MyD88 adaptor function for TLR2, -4, and -9","volume-title":"Eur. J. Immunol.","year":"2008"},{"key":"2026012807071786200_R11","first-page":"355","article-title":"NOD-LRR proteins: role in host-microbial interactions and inflammatory disease","volume-title":"Annu. Rev. Biochem.","year":"2005"},{"key":"2026012807071786200_R12","first-page":"328","article-title":"Naip5\/Birc1e and susceptibility to Legionella pneumophila","volume-title":"Trends Microbiol.","year":"2005"},{"key":"2026012807071786200_R13","first-page":"569","article-title":"Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1\u03b2 via Ipaf","volume-title":"Nat. Immunol.","year":"2006"},{"key":"2026012807071786200_R14","first-page":"5509","article-title":"Host recognition of bacterial muramyl dipeptide mediated through NOD2: implications for Crohn\u2019s disease","volume-title":"J. Biol. Chem.","year":"2003"},{"key":"2026012807071786200_R15","first-page":"8869","article-title":"Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection","volume-title":"J. Biol. Chem.","year":"2003"},{"key":"2026012807071786200_R16","first-page":"279","article-title":"NOD2 and Toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis","volume-title":"PLoS Pathog.","year":"2005"},{"key":"2026012807071786200_R17","first-page":"5127","article-title":"NOD2-deficient mice control infection with Mycobacterium tuberculosis","volume-title":"Infect. Immun.","year":"2007"},{"key":"2026012807071786200_R18","first-page":"36223","article-title":"NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2","volume-title":"J. Biol. Chem.","year":"2007"},{"key":"2026012807071786200_R19","first-page":"e6","article-title":"Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen","volume-title":"PLoS Pathog.","year":"2008"},{"key":"2026012807071786200_R20","first-page":"1713","article-title":"Common nonsynonymous polymorphisms in the NOD2 gene are associated with resistance or susceptibility to tuberculosis disease in African Americans","volume-title":"J. Infect. Dis.","year":"2008"},{"key":"2026012807071786200_R21","first-page":"4015","article-title":"Critical negative regulation of type 1 T cell immunity and immunopathology by signaling adaptor DAP12 during intracellular infection","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012807071786200_R22","first-page":"79","article-title":"Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice","volume-title":"Nature","year":"1999"},{"key":"2026012807071786200_R23","first-page":"581","article-title":"Genetic dissection of immunity to mycobacteria: the human model","volume-title":"Annu. Rev. Immunol.","year":"2002"},{"key":"2026012807071786200_R24","first-page":"1547","article-title":"Uptake of Leishmania major amastigotes results in activation and interleukin 12 release from murine skin-derived dendritic cells: implications for the initiation of anti-Leishmania immunity","volume-title":"J. Exp. Med.","year":"1998"},{"key":"2026012807071786200_R25","first-page":"507","article-title":"Preformed membrane-associated stores of interleukin (IL)-12 are a previously unrecognized source of bioactive IL-12 that is mobilized within minutes of contact with an intracellular parasite","volume-title":"J. Exp. Med.","year":"2000"},{"key":"2026012807071786200_R26","first-page":"1693","article-title":"Mycobacterium tuberculosis and the host response","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012807071786200_R27","first-page":"445","article-title":"Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity","volume-title":"Immunity","year":"2007"},{"key":"2026012807071786200_R28","first-page":"6101","article-title":"Lack of both types 1 and 2 cytokines, tissue inflammatory responses, and immune protection during pulmonary infection by Mycobacterium bovis bacille Calmette-Gu\u00e9rin in IL-12-deficient mice","volume-title":"J. Immunol.","year":"1998"},{"key":"2026012807071786200_R29","first-page":"2249","article-title":"An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection","volume-title":"J. Exp. Med.","year":"1993"},{"key":"2026012807071786200_R30","first-page":"347","article-title":"Host innate immune response to Mycobacterium tuberculosis","volume-title":"J. Clin. Immunol.","year":"2007"},{"key":"2026012807071786200_R31","first-page":"84","article-title":"A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response","volume-title":"Nature","year":"2004"},{"key":"2026012807071786200_R32","first-page":"987","article-title":"Toll-like receptor control of the adaptive immune responses","volume-title":"Nat. Immunol.","year":"2004"},{"key":"2026012807071786200_R33","first-page":"1178","article-title":"IL-1 receptor-mediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012807071786200_R34","first-page":"987","article-title":"MyD88 primes macrophages for full-scale activation by interferon-\u03b3 yet mediates few responses to Mycobacterium tuberculosis","volume-title":"J. Exp. Med.","year":"2003"},{"key":"2026012807071786200_R35","first-page":"800","article-title":"NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses","volume-title":"Nat. Immunol.","year":"2004"},{"key":"2026012807071786200_R36","first-page":"326","article-title":"Identification of the namH gene, encoding the hydroxylase responsible for the N-glycolylation of the mycobacterial peptidoglycan","volume-title":"J. Biol. Chem.","year":"2005"},{"key":"2026012807071786200_R37","first-page":"4501","article-title":"Dissemination of Mycobacterium tuberculosis is influenced by host factors and precedes the initiation of T-cell immunity","volume-title":"Infect. Immun.","year":"2002"},{"key":"2026012807071786200_R38","first-page":"2509","article-title":"Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs","volume-title":"J. Exp. Med.","year":"2008"},{"key":"2026012807071786200_R39","first-page":"2509","article-title":"Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012807071786200_R40","first-page":"1567","article-title":"Visualization of Mycobacterium avium in Crohn\u2019s tissue by oil-immersion microscopy","volume-title":"Microbes Infect.","year":"2007"},{"key":"2026012807071786200_R41","first-page":"607","article-title":"Mycobacterium avium subspecies paratuberculosis and Crohn\u2019s disease: a systematic review and meta-analysis","volume-title":"Lancet Infect. Dis.","year":"2007"},{"key":"2026012807071786200_R42","first-page":"401","article-title":"Detection of Mycobacterium avium subspecies paratuberculosis from patients with Crohn\u2019s disease using nucleic acid-based techniques: a systematic review and meta-analysis","volume-title":"Inflamm. Bowel Dis.","year":"2007"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/10\/7157\/62579778\/8088.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/10\/7157\/62579778\/8088.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:08:03Z","timestamp":1769602083000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/10\/7157\/8007921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2008,11,15]]},"published-print":{"date-parts":[[2008,11,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.10.7157","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,11]]},"published":{"date-parts":[[2008,11]]}}}