CD4+ T cells in Invasive Aspergillosis

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Dr. Amariliz Rivera is a newly appointed, tenure-track, assistant professor at the University of Medicine and Dentistry of New Jersey-New Jersey Medical School (UMDNJ-NJMS). Dr. Rivera is a woman of Puerto Rican descent who is committed to a career as a successful, independent scientist. Her scientific interest lies in performing research with the potential to better the therapeutic options of cancer patients afflicted with opportunistic fungal infections. Dr. Rivera's long-term career goals are: to become a recognized expert in fungal immunology, to establish a successful, well-funded research program and to be a tenured professor with the influence to contribute to diminishing the health disparities in our country. In the short term, she aspires to secure funding to support her new laboratory and its future members and to successfully complete the scientific aims proposed in this application. To attain these goals Dr. Rivera will participate in a variety of programs aimed at promoting her career development including workshops for: grant writing, presentation skills, lab management and leadership. Moreover, Drs. Gause and Salgame will be Amariliz's career development mentors. Both scientists have well-funded laboratories and are tenured-professors who have successfully trained other junior faculty. They will provide personalized advise on her career progression, will review her grants and papers and will guide her through the tenure process. UMDNJ-NJMS is committed to Dr. Rivera's success as a scientist. She has been provided with a fully equipped laboratory and adjacent office as well as with ample space in the vivarium for her mouse strains. More importantly, she will be given protected time to focus on performing research and establishing her laboratory. Dr. Rivera will have access to a diversity of core facilities to aid in her studies and she will be surrounded by a community of fellow scientists with diverse expertise and willingness to help in her career progression. Dr. Rivera's career will also benefit from being a member of the Hispanic Center for Excellence (HCOE) where she will participate in activities specifically designed to enhance the academic performance of individuals from underserved backgrounds. Moreover, through HCOE Dr. Rivera will have the professional support of fellow scientists with common personal backgrounds. The scientific goals of the studies proposed in this K22 application are centered in understanding and exploiting CD4 T lymphocytes in defense against fungal disease. Cancer patients that receive treatment for hematologic malignancies or bone marrow transplantation are at increased risk for developing invasive aspergillosis (IA). IA is a difficult to treat, opportunistic infection with reported mortality rates in excess of 50%. The most common causative agent of IA is Aspergillus fumigatus, a mold frequently present in the environment. Immune based therapies with the potential to benefit IA include vaccination and adoptive T cell transfers. The advancement of such immune-based therapies has been hampered by a lack of understanding of what constitutes protective A.fumigatus-specific, memory CD4 T cell responses and how are they elicited and regulated. In previous studies Dr. Rivera generated a T cell receptor transgenic mouse specific for A. fumigatus (Af3.16-TCR-tg) to track the in vivo activation, trafficking and differentiation of fungus-specific CD4 T cells. Her previous studies dissected the specific contributions of innate cells and innate receptors in shaping fungus-specific CD4 T cell differentiation in response to a primary, pulmonary infection with A.fumigatus spores. In the proposed studies she would further exploit Af3.16-TCR-tg mice to assess the formation of memory CD4 T cell responses to A.fumigatus. The specific aims of the proposed studies are: 1) Determine the impact of immune regulatory mechanisms in controlling fungus-specific CD4 T cell memory formation, 2) To examine the role of innate cell subsets and innate receptors in regulating the expansion and differentiation of fungus- specific CD4 T cell memory responses, 3) To establish optimal adoptive T cell therapies for diverse models of invasive fungal disease. Altogether, the proposed studies would significantly further our understanding of A.fumigatus-specific CD4 T cell memory formation, regulation and potential therapeutic benefit. Moreover, the successful completion of the proposed studies is likely to contribute to the development of novel therapeutic interventions to combat invasive fungal diseases.