Cryptococcus neoformans infections are a significant cause of morbidity and mortality among AIDS patients. Global estimates suggest that one million cases of cryptococcal meningitis occur each year resulting in over 625,000 deaths. Because host immune responses are so vital to the control of cryptococcosis, the overall objective of our laboratory is to determine the mechanism(s) necessary to elicit protective immunity against C. neoformans infections. To this end, the studies conducted during the previous funding period employed a C. neoformans strain engineered to express interferon (IFN)-?, designated H99??, to define protective immune responses against C. neoformans in mice. Importantly, we established for the first time that protective immunity against pulmonary cryptococcosis can be generated in T cell deficient hosts, thus providing "proof of concept" that vaccines targeting C. neoformans can elicit protection against cryptococcosis in immunocompromised patients. Additionally, preliminary results included herein show that signal transducer and activator of transcription 1 (STAT)-mediated classical macrophage (M?) activation is essential for the development of protective immunity against pulmonary cryptococcosis. Moreover, M?s isolated from protectively immunized mice several weeks post-immunization have enhanced pro-inflammatory responses against C. neoformans that are associated with changes in their epigenetic programming. These exciting results support a novel paradigm for "trained" innate immunity against fungal pathogens. Altogether, our studies lead us to hypothesize that STAT1 signaling in M?s is essential for classical M? activation and the induction of vaccine-mediated immunity against pulmonary C. neoformans infection. We plan to test our hypothesis and accomplish our overall objective by pursuing the following Specific Aims: (1) define the role of STAT1 signaling in the initiation of classical M? activation and antimicrobial activity against C. neoformans, (2 determine the mechanism(s) that facilitates STAT1-mediated classical M? activation and protection following immunization with C. neoformans strain H99?, and (3) identify the epigenetic changes within M?s of protectively immunized mice that are associated with protective immunity against C. neoformans.

Public Health Relevance

Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening infections in immune compromised individuals including AIDS patients. The studies proposed in this application are designed to determine a mechanism for inducing protective immunity against C. neoformans infections. My expectation is that these studies will lead to the development of immune-based therapies and/or vaccines to treat or prevent cryptococcosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-K (04))
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Duncan, Rory A
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University of Texas Health Science Center San Antonio
Schools of Arts and Sciences
San Antonio
United States
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Leopold Wager, Chrissy M; Hole, Camaron R; Wozniak, Karen L et al. (2014) STAT1 signaling is essential for protection against Cryptococcus neoformans infection in mice. J Immunol 193:4060-71
Chaturvedi, Ashok K; Hameed, Rumanasma S; Wozniak, Karen L et al. (2014) Vaccine-mediated immune responses to experimental pulmonary Cryptococcus gattii infection in mice. PLoS One 9:e104316
Wozniak, Karen L; Hole, Camaron R; Yano, Junko et al. (2014) Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus neoformans infection. Microbiology 160:1440-52
Leopold Wager, C M; Wormley Jr, F L (2014) Classical versus alternative macrophage activation: the Ying and the Yang in host defense against pulmonary fungal infections. Mucosal Immunol 7:1023-35
Chaturvedi, Ashok K; Weintraub, Susan T; Lopez-Ribot, Jose L et al. (2013) Identification and characterization of Cryptococcus neoformans protein fractions that induce protective immune responses. Proteomics 13:3429-41
Chaturvedi, Ashok K; Wormley Jr, Floyd L (2013) Cryptococcus antigens and immune responses: implications for a vaccine. Expert Rev Vaccines 12:1261-72
Wozniak, Karen L; Hardison, Sarah; Olszewski, Michal et al. (2012) Induction of protective immunity against cryptococcosis. Mycopathologia 173:387-94
Wozniak, Karen L; Hardison, Sarah E; Kolls, Jay K et al. (2011) Role of IL-17A on resolution of pulmonary C. neoformans infection. PLoS One 6:e17204
Wozniak, Karen L; Young, Mattie L; Wormley Jr, Floyd L (2011) Protective immunity against experimental pulmonary cryptococcosis in T cell-depleted mice. Clin Vaccine Immunol 18:717-23
Hardison, Sarah E; Ravi, Sailatha; Wozniak, Karen L et al. (2010) Pulmonary infection with an interferon-gamma-producing Cryptococcus neoformans strain results in classical macrophage activation and protection. Am J Pathol 176:774-85

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