Monoclonal antibodies to inhibit Aspergillus germination

描述（由申请人提供）：烟曲霉是一种普遍存在的真菌病原体，在严重免疫功能低下的患者中引起侵袭性疾病，最常见于重度中性粒细胞减少或接受器官移植的患者。在过去三十年中，侵袭性曲霉病（IA）的发病率稳步上升，目前的死亡率为45-90%。该建议的目标是利用单克隆抗体（MAb 318）促进我们对侵袭性曲霉病中宿主免疫和宿主-病原体相互作用的理解，该单克隆抗体抑制萌发，从孢子形式到菌丝形式所需的阶段转变

DESCRIPTION (provided by applicant): Aspergillus fumigatus, a ubiquitous fungal pathogen, causes invasive disease in severely immunocompromised patients, most often in those with profound neutropenia or who have undergone organ transplantation. The incidence of invasive aspergillosis (IA) has risen steadily over the past three decades, and mortality rates currently range from 45-90%. The goal of this proposal is to advance our understanding of host immunity and host-pathogen interactions in invasive aspergillosis using a monoclonal antibody (MAb 318) that inhibits germination, the phase transition from the spore form to hyphal form that is required for invasion, and prolongs survival in mice with invasive pulmonary aspergillosis. Germination-inhibitory MAbs potentially could be developed for use as immunoprophylactic or diagnostic agents. MAb immunotherapy is being applied with increasing success not only to treatment of refractory or resistant microbial pathogens, but to disease states as diverse as malignancy, asthma and autoimmune disorders. Additionally, identification of fungal molecules bound by protective MAbs may define novel targets for drug development. Three specific aims are proposed: 1. To identify the protein bound by MAb 318 and determine the kinetics of its expression during germination; 2. To understand the interaction between conidia and MAb 318 in vitro in the presence and absence of alveolar macrophages; 3. To understand the mechanism of protective efficacy of passively administered MAbs to the 50 kDa antigen. It is anticipated that this study will identify fungal molecules important for germination and begin to define their interaction with host immune responses.