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In initial studies, we found that the intratracheal (i.t.) administration of<jats:italic>L. pneumophila<\/jats:italic>to mice deficient in TLR9 (TLR9<jats:sup>\u2212\/\u2212<\/jats:sup>) resulted in significantly increased mortality, which was associated with an approximately 10-fold increase in the number of lung CFU compared to that of wild-type BALB\/c mice. Intrapulmonary bacterial challenge in TLR9<jats:sup>\u2212\/\u2212<\/jats:sup>mice resulted in the reduced accumulation of myeloid dendritic cells (DC) and activated CD4<jats:sup>+<\/jats:sup>T cells. Lung macrophages isolated from<jats:italic>Legionella<\/jats:italic>-infected TLR9<jats:sup>\u2212\/\u2212<\/jats:sup>mice displayed the impaired internalization of bacteria and evidence of alternative rather than classical activation, as manifested by the markedly reduced expression of nitric oxide and type 1 cytokines, whereas the expression of Fizz-1 and arginase-1 was enhanced. The adoptive transfer of bone marrow-derived DC from syngeneic wild-type, but not TLR9<jats:sup>\u2212\/\u2212<\/jats:sup>, mice administered i.t. reconstituted anti-legionella immunity and restored the macrophage phenotype in TLR9<jats:sup>\u2212\/\u2212<\/jats:sup>mice. Finally, the i.t., but not intraperitoneal, administration of the TLR9 agonist molecule CpG oligodeoxynucleotide stimulated protective immunity in<jats:italic>Legionella<\/jats:italic>-infected mice. In total, our findings indicate that TLR9 is required for effective innate immune responses against the intracellular bacterial pathogen<jats:italic>L. pneumophila<\/jats:italic>, and approaches to maximize TLR9-mediated responses may serve as a means to augment antibacterial immunity in pneumonia.<\/jats:p>","DOI":"10.1128\/iai.01489-07","type":"journal-article","created":{"date-parts":[[2008,4,22]],"date-time":"2008-04-22T02:42:26Z","timestamp":1208832146000},"page":"2895-2904","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":66,"title":["Toll-Like Receptor 9 Regulates the Lung Macrophage Phenotype and Host Immunity in Murine Pneumonia Caused by<i>Legionella pneumophila<\/i>"],"prefix":"10.1128","volume":"76","author":[{"given":"Urvashi","family":"Bhan","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine, Division of Pulmonary and Critical Care Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenda","family":"Trujillo","sequence":"additional","affiliation":[{"name":"Pathology, University of Michigan Medical Center, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Lyn-Kew","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine, Division of Pulmonary and Critical Care Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Newstead","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine, Division of Pulmonary and Critical Care Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianying","family":"Zeng","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine, Division of Pulmonary and Critical Care Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory M.","family":"Hogaboam","sequence":"additional","affiliation":[{"name":"Pathology, University of Michigan Medical Center, Ann Arbor, Michigan 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur M.","family":"Krieg","sequence":"additional","affiliation":[{"name":"Coley Pharmaceutical Group, Wellesley, Massachusetts 02481"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore J.","family":"Standiford","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine, Division of Pulmonary and Critical Care Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/35021228"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-2478(02)00228-6"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2006.00814.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02049-05"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.9.4878"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.6.3937"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1286-4579(02)00007-2"},{"key":"e_1_3_2_9_2","first-page":"1537","volume":"145","year":"1994","unstructured":"Brieland, J., P. 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