Monocyte-mediated Host Defense against Aspergillus fumigatus

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DESCRIPTION (provided by applicant): This proposal describes a five-year program for the development of a laboratory-based academic career in Infectious Diseases. The candidate, Tobias Hohl, MD, PhD, a fellow in Infectious Diseases, will conduct the program under the supervision of Eric Pamer, MD, Chief of the Infectious Diseases Service at Memorial Sloan-Kettering Cancer Center, and study innate and adaptive immune responses to Aspergillus fumigatus, the most common invasive mold infection in immune compromised patients. The candidate has enlisted the support of an advisory committee of well-known scientists to provide scientific guidance and advice in career development. The research plan is guided by the hypothesis that inflammatory monocytes, a subset of white blood cells, play a pivotal role in host defense against A. fumigatus and that deficiency or dysfunction of these cells promotes pathologic disease states. Two transgenic mouse strains have been developed to test this hypothesis. The first strain labels inflammatory monocytes with a fluorescent protein. The second strain permits toxin-induced ablation of these cells. These mouse strains provide the experimental foundation for the specific aims of this proposal, as follows: (1) to determine the mechanism of pulmonary inflammatory monocyte recruitment during A. fumigatus infection, (2) to examine the effect of inflammatory monocyte depletion on the outcome of respiratory fungal infection and host immune defense mechanisms against A. fumigatus, and (3) to analyze the protective function of inflammatory monocytes during invasive aspergillosis through cell-based adoptive transfer studies. These experiments will provide novel insight into host defenses against fungal spores and invasive disease and provide an experimental basis for adoptive cell transfer experiments to alter the outcome of invasive infection in the most vulnerable host settings. The Infectious Diseases Service and the Immunology Program at MSKCC provide an ideal setting for the candidate to accomplish these goals, develop a scientific identity, and establish the basis for a career in academic medicine.