TRANSCRIPTOME PROFILES OF GENE EXPRESSION IN MONKEY MODELS OF HUMAN MALARIA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。疟疾是一种由蚊子传播的疾病，是一个主要的全球卫生问题，NIAID已经制定了一项议程，将扩大对这一重要病原体的研究努力，包括基因组研究。间日疟原虫是四种人类疟疾寄生虫中最常见的一种，感染广泛分布在亚洲、拉丁美洲、中东、北非和南太平洋地区。食蟹猴是一种与间日疟原虫关系密切的猿类寄生虫，也是间日疟原虫的良好模式。将食蟹猴寄生虫子孢子接种两只猕猴，分别于感染前(基线)、感染后8天(肝期)、寄生虫血症高峰期、首次复发和二次复发时采集外周血单个核细胞(PBMC)，提取RNA。样本在包含22,000多个基因的人类微阵列芯片上运行。使用3000多个差异表达基因的样本聚类显示，两只猴子的样本聚在一起很相似，基线样本与其他样本非常不同，第一次和第二次复发的样本最相似。基因的等级聚类显示，两只猴子的基因表达水平都发生了戏剧性的变化，特别是在肝脏初始阶段和寄生虫病高峰期，许多基因下调。有趣的是，参与防御和免疫的丰富基因的数量在整个过程中都显示出增加的趋势。在这项研究中，我们能够有效地使用猴子疟疾模型来研究宿主基因表达的转录组特征，因为我们感染了未感染疟疾的动物，而伴随感染或营养状况都不是混杂因素，这在疟疾流行地区的人类患者中是预期的。这项工作的出版引起了疟疾研究界的极大兴趣，并于12月应邀向基因组研究所作了介绍。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Malaria, a mosquito borne disease, is a major global health concern and NIAID has developed an agenda that will expand research efforts, including genomic studies, on this important pathogen. P. vivax is the most common of the four human malaria parasites and infection is widespread in Asia, Latin America, the Middle East, North Africa, and the South Pacific. P. cynomolgi, used in this study, is a simian parasite closely related to, and a good model of, P. vivax. Two rhesus macaques were inoculated with sporozoites of P. cynomolgi and RNA was isolated from peripheral blood mononuclear cells (PBMCs) harvested before infection (baseline), after 8 days (liver phase), at the peak parasitemia, at the first relapse, and at the second relapse. Samples were run on a human microarray chip containing over 22,000 genes. Sample clustering, using over 3,000 differentially expressed genes, showed that samples from both monkeys clustered similarly, with baseline samples being very distinct from other samples and the first and second relapse samples being the most similar. Hierarchical clustering of the genes showed dramatic gene expression level changes on both monkeys, especially down regulation of many genes during the initial liver stages and at the peak parasitemia. Interestingly, the number of enriched genes involved in defense and immunity showed increase throughout the time course. In this study we were able to use the monkey malaria model effectively to study the transcriptome profiles of the host gene expression, since we infected malaria-na¿ve animals, and neither concomitant infections nor nutritional status were confounding factors as would be expected in human patients from malaria-endemic areas. The publication of this work has elicited considerable interest from the malaria research community and was the subject of an invited presentation to The Institute of Genomic Research in December.