Genetic mapping identifies novel highly protective antigens for an apicomplexan parasite.
Genetic mapping identifies novel highly protective antigens for an apicomplexan parasite.
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DOI：
10.1371/journal.ppat.1001279
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发表时间：
2011-02-10
期刊：
影响因子：
6.7
通讯作者：
Smith AL
中科院分区：
文献类型：
--
作者：
Blake DP;Billington KJ;Copestake SL;Oakes RD;Quail MA;Wan KL;Shirley MW;Smith AL
顶复门寄生虫是人类和牲畜中无数疾病的罪魁祸首;尽管付出了大量努力，但开发有效的亚单位疫苗仍然是一个长期目标。抗原的复杂性和我们无法从诱导应答的库中识别保护性抗原是新疫苗开发中的严重挑战。使用寄生虫遗传学和选择性屏障与基于群体的遗传指纹相结合，我们已经确定了对家畜最重要的顶复门寄生虫（艾美球虫属）的免疫力。针对的是基因组中的几个离散区域。在此，我们报告了六个基因组区域的鉴定，并在其中两个基因座内鉴定了作为亚单位疫苗赋予免疫力的真正保护性抗原。其中第一个是艾美耳球虫顶端膜抗原-1（AMA-1）的同源物，第二个是以前未表征的基因，我们称之为“免疫映射蛋白-1”（IMP-1）。值得注意的是，AMA-1抗原的同源物对一系列顶复门寄生虫具有保护性，这表明在这一不同的寄生虫群体中可能存在一些共有的保护性抗原的特征。有趣的是，IMP-1抗原的同源物，其对E.最大感染，可以确定在弓形虫和新孢子虫犬。总的来说，这项研究记录了新的保护性抗原的发现，使用基于群体的遗传作图方法与基于保护的候选基因筛选相结合。AMA-1和IMP-1的鉴定代表了开发有效的抗艾美耳球虫亚单位疫苗的实质性一步，并提高了鉴定其他顶复门寄生虫的新抗原的可能性。此外，验证寄生虫遗传学方法，以确定有效的抗原支持其通过在其他寄生虫系统，合法的保护性抗原鉴定是困难的。原生动物寄生虫是人类和牲畜物种中严重疾病的原因。疫苗接种是一种宣布的干预选择与这些感染，但即使经过多年的努力很少有效的疫苗是可用的。鉴定用于包含在亚单位疫苗中的正确抗原是复杂病原体的特殊问题。此外，宿主反应不能区分保护性和非保护性抗原，混淆了有效筛选系统的开发。这项研究代表了使用寄生虫遗传学和免疫作为选择性屏障来寻找免疫靶向的寄生虫基因组部分的工作的高潮。这些研究中使用的病原体（巨型艾美球虫）在牲畜中非常重要，与许多人类病原体（包括导致疟疾的病原体）有关。我们的研究表明，基因组中只有六个区域被免疫靶向，其中两个区域现已被询问以确定保护性抗原编码基因。有趣的是，其中一种（称为AMA-1）具有已知对其他顶复门寄生虫具有保护作用的同源物。这提出了一个有趣的可能性，一组同源抗原可能是保护性的apicomplexan寄生虫和保护性抗原的发现在一个寄生虫可能会产生新的线索，在其他疫苗计划。
Apicomplexan parasites are responsible for a myriad of diseases in humans and livestock; yet despite intensive effort, development of effective sub-unit vaccines remains a long-term goal. Antigenic complexity and our inability to identify protective antigens from the pool that induce response are serious challenges in the development of new vaccines. Using a combination of parasite genetics and selective barriers with population-based genetic fingerprinting, we have identified that immunity against the most important apicomplexan parasite of livestock (Eimeria spp.) was targeted against a few discrete regions of the genome. Herein we report the identification of six genomic regions and, within two of those loci, the identification of true protective antigens that confer immunity as sub-unit vaccines. The first of these is an Eimeria maxima homologue of apical membrane antigen-1 (AMA-1) and the second is a previously uncharacterised gene that we have termed ‘immune mapped protein-1’ (IMP-1). Significantly, homologues of the AMA-1 antigen are protective with a range of apicomplexan parasites including Plasmodium spp., which suggest that there may be some characteristic(s) of protective antigens shared across this diverse group of parasites. Interestingly, homologues of the IMP-1 antigen, which is protective against E. maxima infection, can be identified in Toxoplasma gondii and Neospora caninum. Overall, this study documents the discovery of novel protective antigens using a population-based genetic mapping approach allied with a protection-based screen of candidate genes. The identification of AMA-1 and IMP-1 represents a substantial step towards development of an effective anti-eimerian sub-unit vaccine and raises the possibility of identification of novel antigens for other apicomplexan parasites. Moreover, validation of the parasite genetics approach to identify effective antigens supports its adoption in other parasite systems where legitimate protective antigen identification is difficult. Protozoan parasites are responsible for serious diseases in humans and livestock species. Vaccination is a declared intervention of choice with these infections, but even after many years of effort few effective vaccines are available. Identification of the right antigens for inclusion in sub-unit vaccines is a particular problem with complex pathogens. Moreover, the host response does not discriminate between protective and non-protective antigens, confounding development of effective screening systems. This study represents the culmination of work using parasite genetics and immunity as a selective barrier to find parts of the parasite genome targeted by immunity. The pathogen used in these studies (Eimeria maxima) is very important in livestock and related to a number of human pathogens including those responsible for malaria. Our studies indicate that just six regions in the genome were targeted by immunity and two of these have now been interrogated to determine the protective antigen encoding gene. Interestingly, one of these (called AMA-1) has homologues known to be protective with other apicomplexan parasites. This raises the intriguing possibility that a set of homologous antigens may be protective across the apicomplexan parasites and that protective antigen discovery in one parasite may generate new leads in other vaccine programmes.
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DOI：
10.1073/pnas.0701464104
发表时间：
2007-07-24
影响因子：
11.1
作者：
Dutta, Sheetij;Lee, Seung Yeon;Lanar, David E.
通讯作者：
Lanar, David E.
影响因子：
2
作者：
Blake, DP;Smith, AL;Shirley, MW
通讯作者：
Shirley, MW
影响因子：
14.9
作者：
Letunic I;Doerks T;Bork P
通讯作者：
Bork P
影响因子：
--
作者：
Thomason, Lynn C;Costantino, Nina;Court, Donald L
通讯作者：
Court, Donald L
DOI：
10.1073/pnas.0405097102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Martinelli, A;Cheesman, S;Carter, R
通讯作者：
Carter, R