Immune evasion genes from filarial nematodes

Helminth parasites have large genomes (similar to 10(8) bp) which art: like ly to encode a spectrum of products able to block or divert the host immune response. We have employed three parallel approaches to identify the first generation of 'immune evasion genes from parasites such as the filarial ne matode Brugia malayi. The first strategy is a conventional route to charact erise prominent surface or secreted antigens. In this way we have identifie d a 15-kDa protein. which is located on the surface of both L3 and adult B. malayi, and secreted by these parasites in vitro as a member of the cystat in (cysteine protease inhibitor) family. This product, Bm-CPI-2, blocks con ventional cysteine proteases such as papain, but also the aspariginyl endop eptidase involved in the Class II antigen processing pathway in human B cel ls. In parallel, we identified the major T cell-stimulating antigen from th e microfilarial stage as a serpin (serine protease: inhibitor), Bm-SPN-2. M icrofilariae secrete this product which blocks two key proteases of the neu trophil, a key mediator of inflammation and innate immunity. The second rou te involves a priori hypotheses that helminth parasites encode homologues o f mammalian cytokines such as TGF-P which are members of broad, ancient met azoan gene families. We have identified two TGF-beta homologues in B. malay i, and shown that one form (Bm-TGH-2) is both secreted by adult parasites i n vitro and able to bind to host TGF-beta receptors. Likewise, B. malayi ex presses homologues of mammalian MIF. which are remarkably similar in both s tructure and function to the host protein, even though amino acid identity is only 28%. Finally. we deployed a third method of selecting critical gene s, using an expression-based criterion to select abundant mRNAs taken from key points in parasite life histories. By this means, we have shown that th e major transcript present in mosquito-borne infective larvae, Bm-ALT, is a credible vaccine candidate for use against lymphatic filariasis. while a s econd abundantly-expressed gene. Bm-VAL-1, is similar to a likely vaccine a ntigen being developed against hookworm parasites. (C) 2001 Australian Soci ety for Parasitology Inc. published by Elsevier Science Ltd. All rights res erved.