Restricted Research - Award List, Note/Discussion Page

Fiscal Year: 2014

2071  The University of Texas at San Antonio  (23631)

Principal Investigator: Wormley, Floyd

Total Amount of Contract, Award, or Gift (Annual before 2011): $ 367,500

Exceeds $250,000 (Is it flagged?): Yes

Start and End Dates: 7/1/06 <> 2/28/19

Restricted Research: YES

Academic Discipline: BIOLOGY DEPARTMENT  

Department, Center, School, or Institute: South Texas Center for Emerging Infectious Diseases (STCEID)  

Title of Contract, Award, or Gift: Protective Host Immunity Against Pulmonary Cryptococcosis

Name of Granting or Contracting Agency/Entity: National Institutes of Health
CFDA Link: HHS
93.855

Program Title: none
CFDA Linked: Allergy, Immunology and Transplantation Research

Note:

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 620,000 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 immunosuppressed hosts, thus providing “proof of concept” that vaccines targeting C. neoformans can elicit protection against cryptococcosis in immunocompromised patients. Subsequent studies were aimed at identifying the specific effector cell population that is critical towards mediating protective anti-cryptococcal immune responses. Consequently, we showed that the resolution of pulmonary C. neoformans infection in mice correlated with the development of signal transducer and activator of transcription 1 (STAT1)-mediated classical macrophage (M?) activation. Moreover, preliminary results provided herein demonstrate that M?-specific STAT1 signaling is essential for protection against pulmonary cryptococcosis. In fact, M?s isolated from protectively immunized mice several weeks post-immunization have enhanced responses against C. neoformans that appear to result from changes in their epigenetic programming thus providing a novel paradigm for “trained” innate immunity. Hence, M?s appeared to acquire immunological activity that is typically associated with cells of the classical adaptive immune response. Altogether, these studies lead us to hypothesize that STAT1 signaling is essential for classical M? activation and the induction of vaccine-mediated immunity against pulmonary C. neoformans infection. We plan to test our hypothesis by pursuing the following Specific Aims: (1) to establish that STAT1 activation within M?s is necessary for classical M? activation and protective anti-cryptococcal immune responses, (2) to determine that T cells are required to promote STAT1-mediated classical M? activation and protection following immunization with C. neoformans strain H99?, and (3) to demonstrate that epigenetic changes within M?s of protectively immunized mice are associated with enhanced recall responses against C. neoformans.

Discussion: No discussion notes

 

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