Altered patterns of gene expression underlying the enhanced immunogenicity of radiation-attenuated schistosomes.
Altered patterns of gene expression underlying the enhanced immunogenicity of radiation-attenuated schistosomes.
复制标题
DOI：
10.1371/journal.pntd.0000240
复制
发表时间：
2008-05-21
影响因子：
3.8
通讯作者：
Ivens AC
中科院分区：
文献类型：
--
作者：
Dillon GP;Feltwell T;Skelton J;Coulson PS;Wilson RA;Ivens AC
血吸虫尾蚴只有在暴露于电离辐射（切断其在肺中的迁移）时才能最佳地减弱，才能引发针对挑战感染的高水平保护性免疫。然而，基本的分子机制，负责改变表型的辐射寄生虫，引发保护尚未确定。我们已经使用了一个自定义的微阵列，包括来自肺阶段的寄生虫的探针，以比较模式的基因表达在来自正常和辐照尾蚴的童虫。在RNA提取之前，这些在体外转化并培养4天、7天和10天以对应于引发寄生虫的发育。在辐射损伤后的这些晚期，转录抑制是辐射幼虫的主要特征。个体基因分析显示，在三个时间点，只有七个在辐射与正常幼虫中显著下调;值得注意的是，四种蛋白质产物存在于被膜中或与其膜相关，这可能表明功能受到干扰。使用基因本体论（GO）和随后的基因集富集分析（GSEA）的转录本检索证明在梳理出细微差异方面更有信息量。涉及G蛋白偶联受体的信号通路的缺陷表明寄生虫对环境的感知能力较弱。细胞骨架转录物的减少可能表明结构受损，再加上神经受体转录物的缺乏，可能意味着寄生虫也无法对外部刺激做出正确反应。观察到的转录差异与已知的减毒寄生虫通过皮肤引流淋巴结和肺的延长转运是一致的：寄生虫对免疫系统的延长启动，而不是新抗原的过度表达，因此可以解释辐照疫苗的功效。 曼氏血吸虫（Schistosoma mansoni）是一种血液寄生虫，在整个非洲和南美洲部分地区引起人类血吸虫病。疫苗将加强控制和根除目前依赖单一药物治疗的疾病的努力。虽然制造的疫苗尚未产生高水平的保护，但这可以通过暴露于辐射而丧失能力的感染性寄生虫幼虫来实现。这些虚弱的寄生虫如何能够诱导保护性免疫，而正常的寄生虫却不能，这是我们实验要解决的问题。我们使用基因表达谱技术来比较正常和残疾寄生虫的模式，在这段时间内，它们会触发宿主的免疫反应。我们发现，只有少数基因的差异表达，所有这些都减少了残疾的寄生虫。然而，一种更敏感的检测基因组的技术显示，那些参与神经系统和肌肉功能的基因在残疾的寄生虫中受到抑制。我们认为，这些幼虫的流动性降低，使他们更长的接触免疫系统，从而使一个强大的保护性免疫反应的发展。
Schistosome cercariae only elicit high levels of protective immunity against a challenge infection if they are optimally attenuated by exposure to ionising radiation that truncates their migration in the lungs. However, the underlying molecular mechanisms responsible for the altered phenotype of the irradiated parasite that primes for protection have yet to be identified. We have used a custom microarray comprising probes derived from lung-stage parasites to compare patterns of gene expression in schistosomula derived from normal and irradiated cercariae. These were transformed in vitro and cultured for four, seven, and ten days to correspond in development to the priming parasites, before RNA extraction. At these late times after the radiation insult, transcript suppression was the principal feature of the irradiated larvae. Individual gene analysis revealed that only seven were significantly down-regulated in the irradiated versus normal larvae at the three time-points; notably, four of the protein products are present in the tegument or associated with its membranes, perhaps indicating a perturbed function. Grouping of transcripts using Gene Ontology (GO) and subsequent Gene Set Enrichment Analysis (GSEA) proved more informative in teasing out subtle differences. Deficiencies in signalling pathways involving G-protein–coupled receptors suggest the parasite is less able to sense its environment. Reduction of cytoskeleton transcripts could indicate compromised structure which, coupled with a paucity of neuroreceptor transcripts, may mean the parasite is also unable to respond correctly to external stimuli. The transcriptional differences observed are concordant with the known extended transit of attenuated parasites through skin-draining lymph nodes and the lungs: prolonged priming of the immune system by the parasite, rather than over-expression of novel antigens, could thus explain the efficacy of the irradiated vaccine. Schistosoma mansoni is a blood-dwelling parasitic worm that causes schistosomiasis in humans throughout Africa and parts of South America. A vaccine would enhance attempts to control and eradicate the disease that currently relies on treatment with a single drug. Although a manufactured vaccine has yet to generate high levels of protection, this can be achieved with infective parasite larvae that have been disabled by exposure to radiation. How these weakened parasites are able to induce protective immunity when normal parasites do not, is the question addressed by our experiments. We have used a technique of gene expression profiling to compare the patterns in normal and disabled parasites, over the period when they would trigger an immune response in the host. We found that only a handful of genes were differentially expressed, all of them diminished in the disabled parasite. However, a more sensitive technique to examine groups of genes revealed that those involved in nervous system and muscle function were depressed in the disabled parasites. We suggest that reduced mobility of these larvae permits them longer contact with the immune system, thus enabling a strong protective immune response to develop.
登录
查看更多内容
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
2.4
作者：
MASTIN, AJ;BICKLE, QD;WILSON, RA
通讯作者：
WILSON, RA
影响因子：
2.4
作者：
McKeand, JB
通讯作者：
McKeand, JB
影响因子：
2.4
作者：
HARROP, R;WILSON, RA
通讯作者：
WILSON, RA
影响因子：
4
作者：
Dillon, GP;Feltwell, T;Ivens, AC
通讯作者：
Ivens, AC