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In immunocompromised individuals,<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>can lead to life-threatening meningoencephalitis. Studies using a virulent strain of<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>engineered to produce gamma interferon (IFN-\u03b3), denoted H99\u03b3, demonstrated that protection against pulmonary<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>infection is associated with the generation of a T helper 1 (Th1)-type immune response and signal transducer and activator of transcription 1 (STAT1)-mediated classical (M1) macrophage activation. However, the critical mechanism by which M1 macrophages mediate their anti-<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>activity remains unknown. The current studies demonstrate that infection with<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>strain H99\u03b3 in mice with macrophage-specific STAT1 ablation resulted in severely increased inflammation of the pulmonary tissue, a dysregulated Th1\/Th2-type immune response, increased fungal burden, deficient M1 macrophage activation, and loss of protection. STAT1-deficient macrophages produced significantly less nitric oxide (NO) than STAT1-sufficient macrophages, correlating with an inability to control intracellular cryptococcal proliferation, even in the presence of reactive oxygen species (ROS). Furthermore, macrophages from inducible nitric oxide synthase knockout mice, which had intact ROS production, were deficient in anticryptococcal activity. These data indicate that STAT1 activation within macrophages is required for M1 macrophage activation and anti-<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>activity via the production of NO.<\/jats:p>","DOI":"10.1128\/iai.00935-15","type":"journal-article","created":{"date-parts":[[2015,9,9]],"date-time":"2015-09-09T02:15:51Z","timestamp":1441764951000},"page":"4513-4527","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":88,"title":["STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans"],"prefix":"10.1128","volume":"83","author":[{"given":"Chrissy M.","family":"Leopold Wager","sequence":"first","affiliation":[{"name":"Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA"},{"name":"The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camaron R.","family":"Hole","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA"},{"name":"The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Wozniak","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA"},{"name":"The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal A.","family":"Olszewski","sequence":"additional","affiliation":[{"name":"VA Ann Arbor Health System, University of Michigan Health System, Ann Arbor, Michigan, USA"},{"name":"Division of Pulmonary &amp; Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Mueller","sequence":"additional","affiliation":[{"name":"Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Floyd L.","family":"Wormley","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA"},{"name":"The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198909213211205"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/157.4.624"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(86)90176-2"},{"key":"e_1_3_3_5_2","first-page":"502","article-title":"The pathology of pulmonary cryptococcal infections in the acquired immunodeficiency syndrome","volume":"110","author":"Gal AA","year":"1986","unstructured":"Gal AA, Koss MN, Hawkins J, Evans S, Einstein H. 1986. 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