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In this study, pulmonary infection with the moderately virulent<jats:italic>C. neoformans<\/jats:italic>strain 24067 was used to compare the host resistance phenotype of C57BL\/6J with that of inbred mouse strain SJL\/J. At 7 days or later after infection, C57BL\/6J mice exhibited a significantly greater fungal burden in the lungs than SJL\/J mice. Characterization of the pulmonary innate immune response at 3 h after cryptococcal infection revealed that resistant SJL\/J mice exhibited significantly higher neutrophilia, with elevated levels of inflammatory cytokine tumor necrosis factor alpha (TNF-\u03b1) and keratinocyte-derived chemokine (KC)\/CXCL1 in the airways, as well as increased whole-lung mRNA expression of chemokines KC\/CXCL1, MIP-1\u03b1\/CCL3, MIP-1\u03b2\/CCL4, MIP-2\/CXCL2, and MCP-1\/CCL2 and cytokines interleukin 1\u03b2 (IL-1\u03b2) and IL-1Ra. At 7 and 14 days after infection, SJL\/J mice maintained significantly higher levels of TNF-\u03b1 and KC\/CXCL1 in the airways and exhibited a Th1 response characterized by elevated levels of lung gamma interferon (IFN-\u03b3) and IL-12\/IL-23p40, while C57BL\/6J mice exhibited Th2 immunity as defined by eosinophilia and IL-4 production. Alveolar and resident peritoneal macrophages from SJL\/J mice also secreted significantly greater amounts of TNF-\u03b1 and KC\/CXCL1 following in vitro stimulation with<jats:italic>C. neoformans<\/jats:italic>. Intracellular signaling analysis demonstrated that TNF-\u03b1 and KC\/CXCL1 production was regulated by NF-\u03baB and phosphatidylinositol 3 kinase in both strains; however, SJL\/J macrophages exhibited heightened and prolonged activation in response to<jats:italic>C. neoformans<\/jats:italic>infection compared to that of C57BL\/6J. Taken together, these data demonstrate that an enhanced innate immune response against pulmonary<jats:italic>C. neoformans<\/jats:italic>infection in SJL\/J mice is associated with natural resistance to progressive infection.<\/jats:p>","DOI":"10.1128\/iai.00341-08","type":"journal-article","created":{"date-parts":[[2008,8,5]],"date-time":"2008-08-05T00:40:04Z","timestamp":1217896804000},"page":"4745-4756","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":59,"title":["Enhanced Innate Immune Responsiveness to Pulmonary<i>Cryptococcus neoformans<\/i>Infection Is Associated with Resistance to Progressive Infection"],"prefix":"10.1128","volume":"76","author":[{"given":"Loi\u0308c","family":"Guillot","sequence":"first","affiliation":[{"name":"Centre for the Study of Host Resistance, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott F.","family":"Carroll","sequence":"additional","affiliation":[{"name":"Centre for the Study of Host Resistance, McGill University, Montreal, Canada"},{"name":"Department of Human Genetics, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Homer","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salman T.","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Centre for the Study of Host Resistance, McGill University, Montreal, Canada"},{"name":"Department of Medicine, McGill University, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/314953"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.65.2.525-530.1997"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6346"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01989-05"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425799"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601558"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.23.3.644-651.1979"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.14.7.4912-4919.1994"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.74.1.144-151.2006"},{"key":"e_1_3_2_11_2","doi-asserted-by":"crossref","first-page":"3836","DOI":"10.4049\/jimmunol.156.10.3836","volume":"156","year":"1996","unstructured":"Chaturvedi, V., B. 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