Monoclonal antibodies to inhibit Aspergillus germination

烟曲霉是一种普遍存在的真菌病原菌，可引起严重的侵袭性疾病。 免疫功能低下的患者，最常见的是那些严重的中性粒细胞减少症或接受过器官移植的患者 移植。侵袭性曲霉病(IA)的发病率在过去30年里稳步上升， 目前的死亡率从45%到90%不等。这项建议的目的是增进我们的了解 用单抗研究侵袭性曲霉病的宿主免疫和宿主-病原体相互作用 318)，抑制萌发，即从孢子形态到菌丝形态的阶段转变，这是 侵袭性肺曲霉菌病小鼠的侵袭性，并延长存活时间。萌发抑制单抗 潜在地可以被开发用于免疫预防或诊断试剂。单抗免疫疗法是 不仅在治疗难治或耐药微生物病原体方面取得了越来越大的成功，而且 到各种疾病状态，如恶性肿瘤、哮喘和自身免疫性疾病。此外，识别 被保护性单抗结合的真菌分子可能定义药物开发的新靶点。三个具体的 目的：1.鉴定单抗318结合的蛋白质并测定其动力学 2.了解分生孢子与单抗318的体外相互作用 肺泡巨噬细胞的存在和不存在；3.了解保护作用的机制 被动地给50 kDa抗原注射单抗。预计这项研究将识别真菌 对萌发很重要的分子，并开始定义它们与宿主免疫反应的相互作用。

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. Tounderstand the interaction between conidia and MAb 318 in vitro in the presence and absence of alveolar macrophages; 3. Tounderstand 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.