Monocyte-mediated Host Defense against Aspergillus fumigatus

描述(由申请者提供)：本建议书描述了一项为期五年的传染病实验室学术发展计划。候选人Tobias Hohl，医学博士，传染病研究员，将在纪念斯隆-凯特琳癌症中心传染病服务部主任Eric Pamer医学博士的监督下实施该计划，并研究对烟曲霉的先天和适应性免疫反应，烟曲霉是免疫受损患者中最常见的侵袭性霉菌感染。这位候选人已经得到了一个由知名科学家组成的咨询委员会的支持，以提供职业发展方面的科学指导和建议。这项研究计划的指导假设是，炎性单核细胞是白细胞的一个子集，在宿主抵御烟曲霉菌的过程中发挥着关键作用，这些细胞的缺乏或功能障碍会促进病理疾病状态。已经开发了两个转基因小鼠品系来验证这一假设。第一种菌株用荧光蛋白标记炎性单核细胞。第二种菌株允许毒素诱导的这些细胞的消融。这些小鼠品系为本研究的具体目的提供了实验基础：(1)确定烟曲霉菌感染时肺部炎性单核细胞募集的机制；(2)检测炎性单核细胞耗竭对呼吸道真菌感染结局的影响和宿主对烟曲霉菌的免疫防御机制；(3)通过细胞过继转移研究，分析炎性单核细胞在侵袭性曲霉病中的保护作用。这些实验将为宿主抵御真菌孢子和侵袭性疾病的防御提供新的见解，并为过继细胞转移实验提供实验基础，以改变最脆弱的宿主环境中侵袭性感染的结果。MSKCC的传染病服务和免疫学项目为候选人实现这些目标提供了理想的环境，培养了科学认同感，并为学术医学生涯奠定了基础。

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.