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.
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