title: STAT1 signaling is essential for protection against Cryptococcus neoformans infection in mice.
abstract: Nonprotective immune responses to highly virulent Cryptococcus neoformans strains, such as H99, are associated with Th2-type cytokine production, alternatively activated macrophages, and inability of the host to clear the fungus. In contrast, experimental studies show that protective immune responses against cryptococcosis are associated with Th1-type cytokine production and classical macrophage activation. The protective response induced during C. neoformans strain H99γ (C. neoformans strain H99 engineered to produce murine IFN-γ) infection correlates with enhanced phosphorylation of the transcription factor STAT1 in macrophages; however, the role of STAT1 in protective immunity to C. neoformans is unknown. The current studies examined the effect of STAT1 deletion in murine models of protective immunity to C. neoformans. Survival and fungal burden were evaluated in wild-type and STAT1 knockout (KO) mice infected with either strain H99γ or C. neoformans strain 52D (unmodified clinical isolate). Both strains H99γ and 52D were rapidly cleared from the lungs, did not disseminate to the CNS, or cause mortality in the wild-type mice. Conversely, STAT1 KO mice infected with H99γ or 52D had significantly increased pulmonary fungal burden, CNS dissemination, and 90-100% mortality. STAT1 deletion resulted in a shift from Th1 to Th2 cytokine bias, pronounced lung inflammation, and defective classical macrophage activation. Pulmonary macrophages from STAT1 KO mice exhibited defects in NO production correlating with inefficient inhibition of fungal proliferation. These studies demonstrate that STAT1 signaling is essential not only for regulation of immune polarization but also for the classical activation of macrophages that occurs during protective anticryptococcal immune responses.
authors.affiliation: Department of Biology, University of Texas, San Antonio, TX 78249; South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX 78249;
authors.forename: Chrissy M
authors.initials: CM
authors.lastname: Leopold Wager
authors.affiliation: Department of Biology, University of Texas, San Antonio, TX 78249; South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX 78249;
authors.forename: Camaron R
authors.initials: CR
authors.lastname: Hole
authors.affiliation: Department of Biology, University of Texas, San Antonio, TX 78249; South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX 78249;
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wozniak
authors.affiliation: Veterans Affairs Ann Arbor Health System, University of Michigan Health System, Ann Arbor, MI 48109; and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
authors.affiliation: Department of Biology, University of Texas, San Antonio, TX 78249; South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX 78249; floyd.wormley@utsa.edu.
authors.forename: Floyd L
authors.initials: FL
authors.lastname: Wormley
mesh_terms: D000818:Animals; D003453:Cryptococcosis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D003455:Cryptococcus neoformans / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D009569:Nitric Oxide