Areas of Research: Aspergillus pathogenesis, host response, diagnostics; fungal asthma; aflatoxin
We are developing antibody-based reagents for prevention and diagnosis of disease due to Aspergillus. Invasive aspergillosis occurs mainly in severely immunocompromised hosts and our ability to diagnose or treat this disease with antifungal drugs is limited. Therefore, strategies that enhance the host immune response are an attractive area for development. The laboratory is developing monoclonal antibodies (MAbs) that block or delay germination, the transition from the spore form to hyphal growth that is required for A. fumigatus to invade host tissue. Currently, we are focused on one MAb that we made (MAb 318) that inhibits germination in vitro, alters alveolar macrophage-conidia interactions and prolongs survival in experimental murine pulmonary infection. MAb 318 binds to three A. fumigatus proteins. We are distinguishing which interaction inhibits germination. We also are examining mechanisms by which MAb 318 enhances macrophage function and prolongs survival. Long term goals include determining the suitability of MAbs that bind to this target for passive prophylaxis and of the target itself as a vaccine to prevent disease. We also want to understand the role of this protein during germination and identify additional MAbs that prevent germination, as complete inhibition may require binding to more than one target.
A second area of investigation is development of better antibody-based diagnostic tests for invasive aspergillosis. We currently are employing antibody engineering techniques to enhance the sensitivity and specificity of a test that detects galactomannan, a cell wall and secreted carbohydrate. We also are working to identify novel fungal targets that can distinguish invasive disease from colonization or other forms of aspergillosis. Promising targets will be used to design new assays, with the goal of improving our ability to diagnose human disease.
Fungal products also play important etiological roles in the pathogenesis of asthma. A third area of research is the development of MAbs to fungal or host molecules that can regulate inflammation in response to fungal allergen exposure. Such reagents would have potential for use in combination with currently available asthma therapies, which may allow reduced dependence on some that are associated with broad ranging adverse effects.
We also are developing MAbs to inhibit Aspergillus-derived aflatoxins, common contaminants of stored grains that are potent hepatic carcinogens and acutely toxic. No protective MAbs against aflatoxin exposure have been identified. We made a novel aflatoxin-keyhole limpet hemocyanin conjugate that is potently immunogenic in rats. We currently are making MAbs to aflatoxin B1. MAbs will be tested for their ability to prevent acute toxicity and DNA damage in vitro and in vivo. In the long term, protective MAbs will be assessed for capacity to prevent disease in humans.
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