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Here, we investigated the importance of several immune surveillance pathways in protecting mice against lethal infection by the intracellular pathogen<jats:italic>Legionella pneumophila<\/jats:italic>, the causative agent of a severe pneumonia called Legionnaires' disease. Rip2 and Naip5\/NLRC4 signaling was found to contribute to the innate immune response generated against<jats:italic>L. pneumophila<\/jats:italic>in the lung. Elimination of Rip2 or Naip5\/NLRC4 signaling in MyD88-deficient mice resulted in increased replication and dissemination of<jats:italic>L. pneumophila<\/jats:italic>and higher rates of mortality. Irradiated wild-type mice receiving bone marrow cells from pattern recognition receptor-deficient mice displayed<jats:italic>L. pneumophila<\/jats:italic>infection phenotypes similar to those of donor mice. Rip2 and Naip5\/NLRC4 signaling provided additive effects in protecting MyD88-deficient mice from lethal infection by<jats:italic>L. pneumophila<\/jats:italic>, with the contribution of Naip5\/NLRC4 being slightly greater than that of Rip2. Thus, activation of the Rip2, MyD88, and Naip5\/NLRC4 signaling pathways triggers a coordinated and synergistic response that protects the host against lethal infection by<jats:italic>L. pneumophila<\/jats:italic>. These data provide new insight into how different pattern recognition systems interact functionally to generate innate immune responses that protect the host from lethal infection by activating cellular pathways that restrict intracellular replication of<jats:italic>L. pneumophila<\/jats:italic>and by recruiting to the site of infection additional phagocytes that eliminate extracellular bacteria.<\/jats:p>","DOI":"10.1128\/iai.00243-10","type":"journal-article","created":{"date-parts":[[2010,3,30]],"date-time":"2010-03-30T03:28:48Z","timestamp":1269919728000},"page":"2477-2487","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":51,"title":["Cooperation between Multiple Microbial Pattern Recognition Systems Is Important for Host Protection against the Intracellular Pathogen<i>Legionella pneumophila<\/i>"],"prefix":"10.1128","volume":"78","author":[{"given":"Kristina A.","family":"Archer","sequence":"first","affiliation":[{"name":"Section of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, Connecticut 06536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Ader","sequence":"additional","affiliation":[{"name":"Section of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, Connecticut 06536"},{"name":"Lyon 1 University, Inserm U851, Finovi-Bacterial Pathogenesis and Innate Immunity, National Reference Center for Legionella, Lyon, F-69008, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi S.","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Flavell","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R.","family":"Roy","sequence":"additional","affiliation":[{"name":"Section of Microbial Pathogenesis, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, Connecticut 06536"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80596-8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.1.352-361.2005"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000361"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M604933200"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2008.01234.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02049-05"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01489-07"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.4049\/jimmunol.137.8.2662","volume":"137","year":"1986","unstructured":"Bhardwaj, N., T. 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