Haemoglobin degrading proteases as targets of anti-hookworm vaccines

吸血蠕虫吞食红细胞并在肠道内破坏它们，释放出血红素（Hb）。我们最近表明，犬钩虫利用一组独特的蛋白水解酶，称为血红蛋白酶，消化Hb。所使用的蛋白酶家族和它们起作用的顺序与疟疾寄生虫在其食物液泡中消化Hb所使用的催化途径惊人地相似。我们实验室最近的工作表明，这些蛋白酶通过干扰犬钩虫以血液为食和获得适当营养的能力，可以有效地作为犬钩虫病的疫苗。这反过来又影响了雌虫产卵的能力，从而潜在地破坏了寄生虫的传播。我们现在提议从人类钩虫美洲钩虫中鉴定编码血红蛋白酶的基因，确定Hb降解的有序途径，并探索在钩虫感染和发病动物模型中血红蛋白酶疫苗有效性的体外相关性。

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.