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Mechanisms of environmental sensing and responses by malaria parasites

疟原虫的环境感知和响应机制

基本信息

批准号：
10409750
负责人：
Kirk W Deitsch
金额：
$ 74.59万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409750
关键词：
Adenosylhomocysteinase Affect Anatomy Anopheles Genus Antibodies Antibody titer measurement Antigenic Switching Antigenic Variation Biological Biological Testing Blood Bone Marrow Cells Choline Communicable Diseases Cues Culicidae Culture Media Data Development Disease Environment Enzymes Epigenetic Process Erythrocytes Erythroid Progenitor Cells Event Evolution Exposure to Female Frequencies Future Gene Activation Gene Expression Gene Expression Regulation Gene Family Gene Silencing Genes Genome Glucose Histones Hour Human Immune response In Vitro Infection Invaded Lead Ligase Link Lipids Malaria Measures Mediating Metabolic Metabolic Pathway Metabolism Methyltransferase Modeling Molecular Morbidity - disease rate Nutrient Parasites Pathway interactions Pharmaceutical Preparations Physiological Plague Plasmodium Plasmodium falciparum Positioning Attribute Process Reactive Nitrogen Species Regulation Resistance development Resources Reticulocytes Rodent S-Adenosylmethionine Serine Serum Sex Differentiation Site Surface Antigens Switch Genes Testing Translating Vaccines Work adaptive immune response chronic infection design detection of nutrient environmental change feeding histone methylation histone methyltransferase in vivo lipid metabolism male member methylation pattern mortality mosquito-borne novel strategies precursor cell programs response transmission process vector mosquito

项目摘要

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.

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。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolic regulation of sexual commitment in Plasmodium falciparum.

恶性疟原虫对性承诺的代谢调节。

DOI：
10.1016/j.mib.2020.09.004
发表时间：
2020-12
期刊：
Current opinion in microbiology
影响因子：
5.4
作者：
Neveu G;Beri D;Kafsack BF
通讯作者：
Kafsack BF

Genome-wide profiling of histone modifications in Plasmodium falciparum using CUT&RUN.

DOI：
10.26508/lsa.202201778
发表时间：
2023-01
期刊：
Life science alliance
影响因子：
4.4
作者：
通讯作者：

Safe, Effective, and Inexpensive Clearance of Mycoplasma Contamination from Cultures of Apicomplexan Parasites with Sparfloxacin.

DOI：
10.1128/spectrum.03497-22
发表时间：
2022-10-26
期刊：
Microbiology spectrum
影响因子：
3.7
作者：
通讯作者：

Evolution of transcriptional control of antigenic variation and virulence in human and ape malaria parasites.

DOI：
10.1186/s12862-021-01872-z
发表时间：
2021-07-08
期刊：
BMC ecology and evolution
影响因子：
2.2
作者：
Gross MR;Hsu R;Deitsch KW
通讯作者：
Deitsch KW

The human malaria parasite Plasmodium falciparum can sense environmental changes and respond by antigenic switching.

DOI：
10.1073/pnas.2302152120
发表时间：
2023-04-25
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Schneider, Victoria M.;Visone, Joseph E.;Harris, Chantal T.;Florini, Francesca;Hadjimichael, Evi;Zhang, Xu;Gross, Mackensie R.;Rhee, Kyu Y.;Mamoun, Choukri Ben;Kafsack, Bjorn F. C.;Deitsch, Kirk W.
通讯作者：
Deitsch, Kirk W.