STAT1 signaling within macrophages is required for antifungal activity against Cryptococcus neoformans.

Abstract

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.

• Authors: Chrissy M Leopold Wager, Camaron R Hole, Karen L Wozniak, Michal A Olszewski, Mathias Mueller, Floyd L Wormley Jr
• Journal: Infection and immunity (Infect Immun) Vol. 83 Issue 12 Pg. 4513-27 (Dec 2015) ISSN: 1098-5522 [Electronic] United States
• PMID: 26351277 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Reactive Oxygen Species
• STAT1 Transcription Factor
• Stat1 protein, mouse
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Cryptococcosis (genetics, immunology, microbiology, mortality)
• Cryptococcus neoformans (growth & development, immunology, pathogenicity)
• Gene Expression Regulation
• Host-Pathogen Interactions
• Humans
• Lung (immunology, microbiology, pathology)
• Lung Diseases, Fungal
• Macrophage Activation
• Macrophages, Alveolar (immunology, microbiology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Nitric Oxide (immunology, metabolism)
• Nitric Oxide Synthase Type II (deficiency, genetics, immunology)
• Reactive Oxygen Species (immunology, metabolism)
• STAT1 Transcription Factor (deficiency, genetics, immunology)
• Signal Transduction (immunology)
• Survival Analysis
• Th1-Th2 Balance