Mechanisms of environmental sensing and responses by malaria parasites

项目总结/摘要 疟疾继续在整个发展中世界造成严重的发病率和死亡率。的 对新使用的药物产生耐药性以及缺乏有效的疫苗表明， 在可预见的未来，这一疾病将继续困扰人类。它是由感染 蚊子传播的疟原虫属寄生虫，其中恶性疟原虫负责 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 宿主适应性免疫反应，从而维持可以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充分的机会传播到 通过按蚊吸血增加人类宿主。感染蚊子需要 寄生虫分化为雄性和雌性配子母细胞，这一过程涉及一系列的 基因表达起始于性分化的主要调节因子的表达， PfAP2-G。抗原变异和性别分化都是由基因表达的高度调节机制引起的。 通过组蛋白甲基化的变化在表观遗传学上控制的基因激活和沉默 基因组关键位置的模式。这些基因表达的变化被认为是 随机发生，发生的速度已经进化到为寄生虫提供最好的 主机之间成功传输的机会。在本提案中，我们探讨了以下可能性： 而不是发生随机的，基因表达的变化，导致抗原变异和 性分化是对寄生虫环境变化的反应。对于抗原变异， 我们假设寄生虫可以感知到抗体滴度的上升，这些抗体滴度识别var基因编码的红细胞。 表面抗原，触发表达转换为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侵入红细胞前体细胞， 通过激活编码PfAP 2-G的基因来进行性分化。这 导致网织红细胞和骨髓中配子体的优先发育， 在体内观察。我们已经确定了一种代谢途径，它将这两种反应与细胞周期的变化联系起来。 细胞内储存的通用甲基供体，S-腺苷甲硫氨酸。通过简单的操作， 关键营养素的供应进入这一途径，我们可以触发不同的基因转换， 培养寄生虫的性承诺该项目的具体目标是调查如何 养分利用率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pfap 2-g的组蛋白甲基化模式， 生理条件，触发变异基因转换或性承诺在体内。结果会改变 我们了解疟原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.