STAT1 signaling within macrophages is required for antifungal activity against Cryptococcus neoformans.
Cryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an opportunistic fungal pathogen that primarily affects AIDS patients and patients undergoing immunosuppressive therapy. In immunocompromised individuals, C. neoformans can lead to life-threatening meningoencephalitis. Studies using a virulent strain of C. neoformans engineered to produce gamma interferon (IFN-γ), denoted H99γ, demonstrated that protection against pulmonary C. neoformans 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-C. neoformans activity remains unknown. The current studies demonstrate that infection with C. neoformans strain H99γ 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-C. neoformans activity via the production of NO.
Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
Chrissy M
CM
Leopold Wager
Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
Camaron R
CR
Hole
Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
Karen L
KL
Wozniak
VA Ann Arbor Health System, University of Michigan Health System, Ann Arbor, Michigan, USA Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA.
Michal A
MA
Olszewski
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Mathias
M
Mueller
Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA floyd.wormley@utsa.edu.
Floyd L
FL
Wormley
D000818:Animals; D003453:Cryptococcosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D003455:Cryptococcus neoformans / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008172:Lung Diseases, Fungal; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D016019:Survival Analysis; D058408:Th1-Th2 Balance
D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse