Haemoglobin degrading proteases as targets of anti-hookworm vaccines

食血蠕虫摄取红血球，破坏肠道内的红血球，释放血凝素。我们最近发现，犬钩虫使用一组独特的蛋白水解酶，称为血红蛋白酶，用于消化Hb。所使用的蛋白酶家族及其作用顺序与疟疾寄生虫在其食物液泡中消化HB所使用的明确的催化途径惊人地相似。我们实验室最近的工作表明，这些蛋白水解酶可以干扰犬钩虫吸食血液和获得适当营养的能力，从而有效地作为犬钩虫疾病的疫苗。这反过来会影响雌虫产卵的能力，从而潜在地扰乱寄生虫的传播。我们现在建议从人类钩虫Necator americanus中鉴定编码血红蛋白酶的基因，确定Hb降解的有序途径，并在体外探索血红蛋白酶疫苗在钩虫感染动物模型中的有效性与致病机制的相关性。

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.