Immune evasion genes from filarial nematodes
Immune evasion genes from filarial nematodes
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DOI：
10.1016/s0020-7519(01)00213-2
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发表时间：
2001-07-01
影响因子：
4
通讯作者：
Zang, XX
中科院分区：
文献类型：
--
作者：
Maizels, RM;Gomez-Escobar, N;Zang, XX
蠕虫寄生虫具有大的基因组（类似于10（8）bp），其可能编码能够阻断或转移宿主免疫应答的产物谱。我们已经采用了三种平行的方法来确定第一代的免疫逃避基因的寄生虫，如丝虫马来丝虫。第一种策略是常规途径以抑制突出的表面或分泌的抗原。通过这种方式，我们鉴定了一种15 kDa的蛋白质。其位于L3和成人B的表面上。Malayi，并且作为半胱氨酸蛋白酶抑制剂（半胱氨酸蛋白酶抑制剂）家族的成员由这些寄生虫在体外分泌。该产物Bm-CPI-2不仅阻断常规半胱氨酸蛋白酶如木瓜蛋白酶，而且阻断参与人B细胞中II类抗原加工途径的精氨酸内肽酶。同时，我们确定了主要的T细胞刺激抗原从微丝蚴阶段作为丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶：抑制剂），Bm-SPN-2。微丝蚴分泌这种产物，其阻断中性粒细胞的两种关键蛋白酶，这是炎症和先天免疫的关键介质。第二种途径涉及一个先验的假设，即蠕虫寄生虫编码同源的哺乳动物细胞因子，如TGF-β的成员广泛，古老的后生动物基因家族。我们在B中鉴定了两种TGF-β同系物。malayi，并显示一种形式（Bm-TGH-2）既由体外成虫分泌，又能够结合宿主TGF-β受体。我也是，B。malayi表达哺乳动物MIF的同源物。其在结构和功能上与宿主蛋白质非常相似，尽管氨基酸同一性仅为28%。终于来了我们采用了第三种选择关键基因的方法，使用基于表达的标准来选择从寄生虫生活史的关键点提取的丰富mRNA。通过这种方法，我们已经表明，主要的转录本存在于蚊媒感染性幼虫，Bm-ALT，是一个可靠的候选疫苗用于抗淋巴丝虫病。而第二个基因被大量表达。Bm-VAL-1类似于针对钩虫寄生虫开发的可能的疫苗抗原。(C)2001年澳大利亚寄生虫学学会有限公司由Elsevier Science Ltd.出版，版权所有。
Helminth parasites have large genomes (similar to 10(8) bp) which art: likely 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 nematode Brugia malayi. The first strategy is a conventional route to characterise prominent surface or secreted antigens. In this way we have identified 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 cystatin (cysteine protease inhibitor) family. This product, Bm-CPI-2, blocks conventional cysteine proteases such as papain, but also the aspariginyl endopeptidase involved in the Class II antigen processing pathway in human B cells. In parallel, we identified the major T cell-stimulating antigen from the microfilarial stage as a serpin (serine protease: inhibitor), Bm-SPN-2. Microfilariae secrete this product which blocks two key proteases of the neutrophil, a key mediator of inflammation and innate immunity. The second route involves a priori hypotheses that helminth parasites encode homologues of mammalian cytokines such as TGF-P which are members of broad, ancient metazoan gene families. We have identified two TGF-beta homologues in B. malayi, and shown that one form (Bm-TGH-2) is both secreted by adult parasites in vitro and able to bind to host TGF-beta receptors. Likewise, B. malayi expresses homologues of mammalian MIF. which are remarkably similar in both structure and function to the host protein, even though amino acid identity is only 28%. Finally. we deployed a third method of selecting critical genes, using an expression-based criterion to select abundant mRNAs taken from key points in parasite life histories. By this means, we have shown that the major transcript present in mosquito-borne infective larvae, Bm-ALT, is a credible vaccine candidate for use against lymphatic filariasis. while a second abundantly-expressed gene. Bm-VAL-1, is similar to a likely vaccine antigen being developed against hookworm parasites. (C) 2001 Australian Society for Parasitology Inc. published by Elsevier Science Ltd. All rights reserved.