Haemoglobin degrading proteases as targets of anti-hookworm vaccines

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Blood-feeding worms ingest red blood cells and disrupt them in the intestine, releasing haemogobin (Hb). We have recently shown that canine hookworms employ a battery of distinct proteolytic enzymes, termed haemoglobinases, which digest Hb. The families of proteases used and the order in which they act are strikingly similar to the defined catalytic pathway used by the malaria parasite to digest Hb in its food vacuole. Recent work from our laboratory has shown that these proteases are effective as vaccines against canine hookworm disease by interfering with the worm's ability to feed on blood and obtain suitable nutrition. This in turn affects the ability of female worms to lay eggs, thereby potentially disrupting transmission of the parasites. We now propose to identify the genes encoding haemoglobinases from the human hookworm, Necator americanus, determine the ordered pathway of Hb degradation and explore in vitro correlates of the effectiveness of a haemoglobinase vaccine in animal models of hookworm infection and pathogenesis.