Filarial nematodes of man, like most helminth parasites, are long-lived organisms which persist in the mammalian host despite a vigorous and sustained immune response. The ability to neutralize or subvert host immunity is thus crucial to their survival. Characterization of parasite molecules involved in this process and dissection of the associated mechanisms will not only provide a focal point for the development of chemotherapy and immunoprophylaxis against filariasis, but will also provide basic information on immune effector mechanisms against complex multicellular parasites. We intend to focus upon anti-oxidant enzymes, which we propose are a primary line of defence against host immunity and the project will include studies on the three major filarial nematode parasites of man: onchocerca volvulus, Wuchereria bancrofti and Brugia malayi.
We will complete the characterization of the genes for glutathione peroxidase (GSHPX) and superoxide dismutase (SOD) from 0. volvulus and Brugia, determine whether these encode distinct cytosolic and secreted enzymes and define (where possible) their expression in different stages. We will then develop antibody reagents to expressed gene products and utilize these to determine the localization of the native enzymes in different stages via immuno-electronmicroscopy. Enzyme secretion will be monitored in vivo with these reagents, and measured both biochemically and immunologically in vitro. The immune response to anti-oxidants will be assessed in Indian patients infected with W. bancrofti, most specifically by measuring antibodies which inhibit and/or bind parasite enzymes. The putative protective role of these enzymes against damage and killing by reactive oxygen metabolites will be assessed in vitro, primarily with different stages of B. malayi, by measuring the extent and site of lipid peroxidation in relation to the activity of parasite anti-oxidants. Particular attention will be focused upon the cuticle, and freeze fracture analysis will be employed to assess immune-mediated damage to cuticular membrane structures. The effect of enzyme inhibitors and inhibitory antibodies will also be determined, which will define the suitability of these molecules as targets oE chemo- or immuno-prophylaxis.
Fields of science
Topic(s)Data not available
Call for proposalData not available
Funding SchemeCSC - Cost-sharing contracts
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221005 Varanasi - Utta Pradesh
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SW7 2AY London
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