Cryptococcus neoformans infections among HIV-infected individuals in the United States occurs at a prevalence rate of 5-10% and is a leading mycological cause of morbidity and mortality among AIDS patients. Studies have suggested that cell-mediated immunity (CMI) by T helper (Th) 1-type CD4+ T cells is the predominant host defense mechanism against C. neoformans infections. However, the detailed immunological response that would elicit protection against cryptococcal relapse or reinfection is yet to be defined. In our preliminary studies, we have shown that an experimental pulmonary infection with an interferon gamma (IFN-g)-producing C. neoformans strain in mice results in the induction of Th1-type CMI responses and resolution of the acute infection. Furthermore, we have for the first time demonstrated that prior challenge with an IFN-g-producing C. neoformans strain results in complete (100%) protection against a second pulmonary challenge with a pathogenic C. neoformans strain. Based on these results, we hypothesize that C. neoformans strains engineered to produce IFN-g can be used to determine the mechanism(s) involved in protective host immunity against pathogenic pulmonary C. neoformans infections. Therefore, we propose to use this model system to analyze protective anti-cryptococcal host immune responses using the following """"""""Specific Aims"""""""": (1) To characterize the impact of local cryptococcal IFN-g production on the induction of host immunity against pulmonary cryptococcosis. (2) To determine the immune mechanism(s) that is responsible for resistance against re-infection with a pathogenic C. neoformans strain. (3) To evaluate the local pathology and cellular composition of the inflammatory response in mice resistant and susceptible to experimental pulmonary cryptococcosis. (4) To determine if the route of challenge with the IFN-g producing C. neoformans strain influences the development of protective immunity against pulmonary or disseminated C. neoformans infections. Cryptococcus neoformans is an opportunistic fungus that may cause life-threatening infections of the brain in individuals with suppressed immune systems. I am proposing to perform studies to define the parameters of which protective immune responses can be generated against C. neoformans infections. My expectation is that these studies will lead to the development of therapies and/or vaccines to treat or prevent fungal infections in immune compromised individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071752-04
Application #
7775100
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Duncan, Rory A
Project Start
2007-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$343,559
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
Caballero Van Dyke, Marley C; Wormley Jr, Floyd L (2017) A Call to Arms: Quest for a Cryptococcal Vaccine. Trends Microbiol :
Van Dyke, Marley C Caballero; Chaturvedi, Ashok K; Hardison, Sarah E et al. (2017) Induction of Broad-Spectrum Protective Immunity against Disparate Cryptococcus Serotypes. Front Immunol 8:1359
Campuzano, Althea; Castro-Lopez, Natalia; Wozniak, Karen L et al. (2017) Dectin-3 Is Not Required for Protection against Cryptococcus neoformans Infection. PLoS One 12:e0169347
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
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
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
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
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

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