Mechanisms of environmental sensing and responses by malaria parasites

项目摘要/摘要 疟疾继续在整个发展中世界造成相当大的发病率和死亡率。这个 对新部署的药物产生抗药性以及缺乏有效的疫苗表明 在可预见的未来，这种疾病将继续困扰人类。它是由感染了 蚊媒疟原虫属的寄生虫，恶性疟原虫属负责 这种疾病最严重的形式。这些寄生虫利用一种称为抗原变异的过程来避免 宿主的适应性免疫反应，从而维持可持续的长期、慢性感染 一年多了。这种漫长的感染为寄生虫提供了大量的传播机会 通过按蚊的血液摄食增加人类宿主。感染蚊子需要 寄生虫分化为雄配子体和雌配子体的过程，这一过程涉及一系列 基因表达开始于性别分化的主要调节因子，称为 PfAP2-G。抗原变异和性别分化都是高度调控的机制所致 通过组蛋白甲基化改变在表观遗传学上控制的基因激活和沉默 基因组中关键位置的模式。这些基因表达的变化被认为是 随机发生的，发生的速度已经进化到为寄生虫提供最好的 在主机之间成功传输的机会。在这项提案中，我们探讨了以下可能性 基因表达的变化不是随机发生的，而是导致抗原变异和 性分化是由于寄生虫环境的变化而发生的。对于抗原变异， 我们假设寄生虫可以感知到识别var基因编码的红细胞的抗体滴度的上升。 表面抗原，触发表达切换到var基因家族的替代成员。 类似地，我们假设寄生虫可以感知它们何时入侵红细胞前体细胞和 通过激活编码PfAP2-G的基因来实现性别分化。这 导致配子体在网织红细胞和骨髓中优先发育，正如已经发生的那样 活体观察。我们已经确定了一条代谢途径，将这两种反应与 通用甲基供体S-腺苷蛋氨酸的细胞内储存。通过简单的操作 进入这一途径的关键营养物质的可用性，我们可以触发var基因切换或 培养寄生虫的性行为承诺。该项目的具体目标旨在调查如何 营养可利用性的变化转化为细胞内S-腺苷甲硫氨酸的变化 这些变化影响var基因和pfap2-g上的组蛋白甲基化模式，并确定 在体内触发var基因切换或性承诺的生理条件。结果将会改变 我们理解疟疾寄生虫如何感知和应对环境变化的方式。

Project Summary/Abstract Malaria continues to cause substantial morbidity and mortality throughout the developing world. The development of resistance to newly deployed drugs as well as the lack of an effective vaccine indicate that this disease will continue to plague mankind for the foreseeable future. It is caused by infection with mosquito-borne parasites of the genus Plasmodium, with the species P. falciparum being responsible for the most severe form of the disease. These parasites utilize a process called antigenic variation to avoid the adaptive immune response of their host and thus maintain long-term, chronic infections that can last over a year. Such lengthy infections provide the parasites with ample opportunities to be transmitted to additional human hosts through blood feeding by Anopheline mosquitoes. Infection of mosquitoes requires the differentiation of parasites into male and female gametocytes, a process that involves a cascade of gene expression that initiates with the expression of a master regulator of sexual differentiation called PfAP2-G. Both antigenic variation and sexual differentiation result from highly regulated mechanisms of gene activation and silencing that are controlled epigenetically through changes in histone methylation patterns at key positions in the genome. These changes in gene expression have been presumed to happen stochastically, occurring at a rate that has evolved to provide the parasites with the best opportunity for successful transmission between hosts. In this proposal, we explore the possibility that rather than occurring stochastically, changes in gene expression that lead to both antigenic variation and sexual differentiation occur in response to changes in the parasite's environment. For antigenic variation, we hypothesize that parasites can sense rising antibody titers that recognize var gene-encoded RBC surface antigens, triggering switching of expression to alternative members of the var gene family. Similarly, we hypothesize that parasites can sense when they invade erythrocyte precursor cells and respond by committing to sexual differentiation through the activation of the gene encoding PfAP2-G. This results in preferential development of gametocytes in reticulocytes and in the bone marrow, as has been observed in vivo. We have identified a metabolic pathway that links both of these responses to changes in intracellular stores of the universal methyl donor, S-adenosylmethionine. Through simple manipulations of the availability of key nutrients that feed into this pathway, we can trigger either var gene switching or sexual commitment in cultured parasites. The specific aims of the project are designed to investigate how changes in nutrient availability are translated into changes in intracellular S-adenosylmethionine, how these changes affect histone methylation patterns at var genes and pfap2-g, and to identify the physiological conditions that trigger var gene switching or sexual commitment in vivo. The results will alter the way we understand how malaria parasites sense and respond to changes in their environment.