Aspergillus fumigatus, a ubiquitous fungal pathogen, causes invasive disease in severely immunocompromised patients, most often in those with profound neutropenia. The incidence of invasive aspergillosis has risen steadily over the past three decades, and mortality rates currently range from 45-90 percent. The goal of this proposal is to advance our understanding of host immunity and host-pathogen interactions in invasive aspergillosis by identifying A. fumigatus antigens that elicit protective antibody immunity. The approach is to develop monoclonal antibodies (MAbs) to selected A. fumigatus antigens that will modify the course of infection to the benefit of the host. MAbs so identified will be used to study both effective host responses to A. fumigatus and host-pathogen interactions. Beneficial MAbs potentially could be developed for use as immunotherapeutic 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. This proposal includes two strategies, study of MAbs to a defined fungal target, the dipeptidyl peptidase V (DPP V) of A. fumigatus, and development of agents that prevent the transition of A. fumigatus from the conidial (spore) form to the hyphal form that is required for invasion.
Three specific aims are proposed: 1. To determine the protective efficacy of MAbs to A. fumigatus DPP V; 2. To generate and characterize in vitro MAbs to A. fumigatus that prevent germination; 3. To determine the biological activity of MAbs generated in Aim 2 in murine models of invasive aspergillosis. It is anticipated that this study will identify important targets for further investigation.
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