Secretion of Protective Antigens by Tissue-Stage Nematode Larvae Revealed by Proteomic Analysis and Vaccination-Induced Sterile Immunity
Secretion of Protective Antigens by Tissue-Stage Nematode Larvae Revealed by Proteomic Analysis and Vaccination-Induced Sterile Immunity
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DOI：
10.1371/journal.ppat.1003492
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发表时间：
2013-08-01
期刊：
影响因子：
6.7
通讯作者：
Maizels, Rick M.
中科院分区：
文献类型：
--
作者：
Hewitson, James P.;Ivens, Al C.;Maizels, Rick M.
胃肠道线虫寄生虫感染了超过10亿人，几乎没有证据表明产生了杀菌免疫。这些蠕虫高度适应它们的哺乳动物宿主，通过连续的生态位遵循发育程序，同时有效地下调宿主的免疫反应。例如，多回螺虫的幼虫在肠粘膜下层包囊，然后以成虫的形式出现在十二指肠腔内。成人释放免疫调节排泄分泌(ES)产物，但用成年多回ES免疫的小鼠对挑战感染完全免疫。肠壁第四期(L4)幼虫的ES产物在宿主-寄生虫相互作用中也同样重要，因为它们很容易产生对抗感染的无菌免疫，而从卵期释放的物质是无效的。L4ES的蛋白质组学分析识别保护性抗原靶标以及潜在的组织相免疫调节分子，使用成体ES蛋白质组和多脑回卵子释放物质的图谱作为比较器。虽然L4和成体ES之间共有135个蛋白质，但有72个是L4 ES特有的；L4特有的蛋白质对应于那些转录仅限于幼虫阶段的蛋白质，而共有的蛋白质通常由所有生命周期形式转录。有两个蛋白家族在L4分泌组中有更高的表达，Sushi结构域与补体调节相关，ShK/SXC结构域与一种毒素干扰T细胞信号有关。成体ES和L4 ES都含有广泛但不同的毒液变应原/钩虫分泌蛋白样蛋白(Val)成员，其中乙酰胆碱酯酶(ACE)和APY-3在L4 ES中尤其丰富。用L4免疫的小鼠和成年ES的血清抗体对Val-1蛋白和ACE-1反应强烈，表明这两种抗原是这种肠道线虫的主要疫苗靶标。因此，我们定义了一个广泛和新颖的多回蛋白谱系，这些蛋白与免疫调节和保护性免疫密切相关。
Gastrointestinal nematode parasites infect over 1 billion humans, with little evidence for generation of sterilising immunity. These helminths are highly adapted to their mammalian host, following a developmental program through successive niches, while effectively down-modulating host immune responsiveness. Larvae of Heligmosomoides polygyrus, for example, encyst in the intestinal submucosa, before emerging as adult worms into the duodenal lumen. Adults release immunomodulatory excretory-secretory (ES) products, but mice immunised with adult H. polygyrus ES become fully immune to challenge infection. ES products of the intestinal wall 4th stage (L4) larvae are similarly important in host-parasite interactions, as they readily generate sterile immunity against infection, while released material from the egg stage is ineffective. Proteomic analyses of L4 ES identifies protective antigen targets as well as potential tissue-phase immunomodulatory molecules, using as comparators the adult ES proteome and a profile of H. polygyrus egg-released material. While 135 proteins are shared between L4 and adult ES, 72 are L4 ES-specific; L4-specific proteins correspond to those whose transcription is restricted to larval stages, while shared proteins are generally transcribed by all life cycle forms. Two protein families are more heavily represented in the L4 secretome, the Sushi domain, associated with complement regulation, and the ShK/SXC domain related to a toxin interfering with T cell signalling. Both adult and L4 ES contain extensive but distinct arrays of Venom allergen/Ancylostoma secreted protein-Like (VAL) members, with acetylcholinesterases (ACEs) and apyrase APY-3 particularly abundant in L4 ES. Serum antibodies from mice vaccinated with L4 and adult ES react strongly to the VAL-1 protein and to ACE-1, indicating that these two antigens represent major vaccine targets for this intestinal nematode. We have thus defined an extensive and novel repertoire of H. polygyrus proteins closely implicated in immune modulation and protective immunity.