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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI071752-06A1
Application #
8752693
Study Section
Special Emphasis Panel (ZRG1-AARR-K (04))
Program Officer
Duncan, Rory A
Project Start
2006-07-01
Project End
2019-02-28
Budget Start
2014-03-15
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$367,500
Indirect Cost
$117,500
Name
University of Texas Health Science Center San Antonio
Department
None
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
Leopold Wager, Chrissy M; Hole, Camaron R; Wozniak, Karen L et al. (2016) Cryptococcus and Phagocytes: Complex Interactions that Influence Disease Outcome. Front Microbiol 7:105
Eastman, Alison J; He, Xiumiao; Qiu, Yafeng et al. (2015) Cryptococcal heat shock protein 70 homolog Ssa1 contributes to pulmonary expansion of Cryptococcus neoformans during the afferent phase of the immune response by promoting macrophage M2 polarization. J Immunol 194:5999-6010
Wozniak, Karen L; Olszewski, Michal A; Wormley Jr, Floyd L (2015) Molecules at the interface of Cryptococcus and the host that determine disease susceptibility. Fungal Genet Biol 78:87-92
Leopold Wager, Chrissy M; Hole, Camaron R; Wozniak, Karen L et al. (2015) STAT1 signaling within macrophages is required for antifungal activity against Cryptococcus neoformans. Infect Immun 83:4513-27
Zhai, Bing; Wozniak, Karen L; Masso-Silva, Jorge et al. (2015) Development of protective inflammation and cell-mediated immunity against Cryptococcus neoformans after exposure to hyphal mutants. MBio 6:e01433-15
Leopold Wager, Chrissy M; Wormley Jr, Floyd L (2015) Is Development of a Vaccine against Cryptococcus neoformans Feasible? PLoS Pathog 11:e1004843
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
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; 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

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