Parasite and host cell factors involved in the formation and persistence of Plasmodium vivax hypnozoites
寄生虫和宿主细胞因子参与间日疟原虫休眠子的形成和持续存在
基本信息
- 批准号:10564073
- 负责人:
- 金额:$ 82.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-09 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AntimalarialsBiologicalBiologyBloodCellsCellular biologyClinicalComplexCulicidaeDataDevelopmentEnvironmentEpidemiologyErythrocytesEventFeedsFrequenciesGRP94Gene DeletionGene ExpressionGene Expression ProfilingGene Transfer TechniquesGenesGenomeGoalsGrowthHepatocyteHost DefenseHumanIn VitroInfectionIntegration Host FactorsKnock-outKnowledgeLaboratoriesLiverMalariaMediatingMessenger RNAMetabolismModelingMolecularMonkeysMusNational Institute of Allergy and Infectious DiseaseParasitesPathogenicityPersonsPhasePhenotypePlasmodiumPlasmodium vivaxPrimary InfectionProcessRecombinantsRegulationRelapseReporter GenesResearchRodentRoleSaimiriSalivary GlandsShapesSmall Interfering RNASourceSporozoitesSystemTechniquesTransfectionTransgenic OrganismsTranslational RepressionVivax MalariaWorkenhancer-binding protein AP-2humanized mouseinsightknock-downliver infectionmalaria infectionmouse modeloverexpressionpathogenrelapse preventionresponsestress granulesymptom treatmenttargeted treatmenttooltranscription factortransgene expressionvector control
项目摘要
This application is in response to the NIAID RFA-AI-21-075 entitled “Identification and Characterization of
Persistence Mechanisms of Select Protozoan Pathogens”, which explicitly states the study of P. vivax
hypnozoites as a research objective. P. vivax malaria burdens people within a wide global range and is more
pathogenic than previously appreciated. The parasite’s epidemiology and clinical impact is governed by latent
liver stages called hypnozoites, which are the source of relapsing blood stage infection. The molecular regulation
of hypnozoite stage formation, persistence and activation in hepatocytes has until recently remained unstudied,
mainly due to the lack of laboratory tools for this parasite. This has changed of the past ten years with the
development of our robust human liver-chimeric mouse model (FRG huHep mouse) that enables the detailed
analysis of hypnozoite formation and persistence as well the occurrence of relapses and robust in vitro primary
hepatocyte models of infection. In addition, with partners we have recently developed the genetically defined P.
vivax Chesson strain for use in hypnozoite studies, replacing complex field-isolate derived sporozoites for
infection. With these tools, the goals of this application are the identification of the parasite molecular drivers of
hypnozoite formation and persistence and host hepatocyte factors that impact hypnozoite formation and
persistence. We will achieve these goals through three independent but complementary aims. In Aim 1 we will
generate and interrogate hypnozoite gene expression data with emphasis on factors that are known to regulate
quasi-persistence in salivary gland sporozoites. Candidate factors such as AP2 transcription factors, the
eIF2a/IK2/UIS2 translational repression system and the, SAP1 and PUF stress granule mRNA storage system
will undergo comprehensive examination in P. vivax hypnozoites. Implicated factors that might drive and maintain
hypnozoite persistence will then be functionally interrogated using transgene expression and knockout as well
as overexpression in a rodent malaria model. In aim 2, we will establish a P. vivax transgenesis system using
sporozoite transfection and the Saimiri monkey infection model to establish P. vivax reporter gene-expressing
parasite lines, including a line that expresses a hypnozoite-specific marker GRP94, recently identified by us. We
will also functionally analyze factors in P. vivax that show strong persistence phenotypes in aim 1 to directly
interrogate their role in hypnozoite formation and persistence. In aim 3, we will identify and interrogate host
factors with emphasis on host defenses and metabolism in hypnozoite-infected hepatocytes. Host factors that
are associated with hypnozoite formation and persistence will be functionally analyzed using siRNA-mediated
knockdown and overexpression techniques in an in vitro hypnozoite infection model. Together, this application
will gain unprecedented insights into the parasite-intrinsic molecular regulation of liver stage latency as well as
the host factors that can further shape the latency phenotype. The findings might lead to the identification of new
parasite-targeted and host-targeted therapeutics that prevent relapsing malaria infection.
本申请是为了响应 NIAID RFA-AI-21-075,题为“Identification and Characterization of
Select Protozoan Pathogens 的持久性机制”,其中明确阐述了对间日疟原虫的研究
间日疟原虫作为研究目标,给全球范围内的人们带来了负担。
寄生虫的流行病学和临床影响取决于潜在的致病性。
肝阶段称为休眠子,是复发性血阶段感染的分子调节源。
直到最近,肝细胞中催眠阶段的形成、持续性和激活仍未得到研究,
主要是由于缺乏针对这种寄生虫的实验室工具,这种情况在过去十年中发生了变化。
开发我们强大的人肝嵌合小鼠模型(FRG huHep 小鼠),使详细的
分析催眠体的形成和持续性以及复发和强体外原发性的发生
此外,我们最近与合作伙伴开发了基因定义的 P.
vivax Chesson 菌株用于催眠子研究,取代复杂的场分离衍生子孢子
通过这些工具,该应用的目标是识别感染的寄生虫分子驱动因素。
催眠子的形成和持续性以及影响催眠子形成和的宿主肝细胞因素
我们将通过三个独立但互补的目标来实现这些目标。
生成和询问催眠基因表达数据,重点关注已知的调节因素
唾液腺子孢子中的准持久性候选因子,例如 AP2 转录因子、
eIF2a/IK2/UIS2 翻译抑制系统以及 SAP1 和 PUF 应激颗粒 mRNA 存储系统
将在间日疟原虫休眠子中进行全面检查,这些因素可能会驱动和维持。
然后,将使用转基因表达和基因敲除对催眠体的持久性进行功能性询问
在啮齿动物疟疾模型中的过度表达在目标 2 中,我们将使用间日疟原虫转基因系统。
子孢子转染和Saimiri猴感染模型建立间日疟原虫报告基因表达
寄生虫品系,包括我们最近鉴定出的表达催眠体特异性标记物 GRP94 的品系。
还将对目标 1 中表现出强持久性表型的间日疟原虫中的因子进行功能分析,以直接
探究它们在催眠体形成和持久性中的作用 在目标 3 中,我们将识别并探究宿主。
强调宿主防御和受休眠子感染的肝细胞代谢的因素。
与催眠体的形成和持久性相关,将使用 siRNA 介导的功能进行分析
体外休眠子感染模型中的敲低和过表达技术一起,该应用。
将获得对肝脏阶段潜伏期的寄生虫内在分子调节以及
可以进一步塑造潜伏表型的宿主因素,这些发现可能有助于识别新的潜伏表型。
预防疟疾感染复发的针对寄生虫和针对宿主的治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Stefan HI Kappe其他文献
Stefan HI Kappe的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Stefan HI Kappe', 18)}}的其他基金
Biologically informed design of CD8+ T cell-dependent pre-erythrocytic stage malaria vaccines
CD8 T 细胞依赖性红细胞前阶段疟疾疫苗的生物学知情设计
- 批准号:
10341058 - 财政年份:2021
- 资助金额:
$ 82.34万 - 项目类别:
Biologically informed design of CD8+ T cell-dependent pre-erythrocytic stage malaria vaccines
CD8 T 细胞依赖性红细胞前阶段疟疾疫苗的生物学知情设计
- 批准号:
10558591 - 财政年份:2021
- 资助金额:
$ 82.34万 - 项目类别:
Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects
评估 SARS-CoV-2 感染人类受试者持久保护性免疫力的决定因素
- 批准号:
10265628 - 财政年份:2020
- 资助金额:
$ 82.34万 - 项目类别:
Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects
评估 SARS-CoV-2 感染人类受试者持久保护性免疫力的决定因素
- 批准号:
10375774 - 财政年份:2019
- 资助金额:
$ 82.34万 - 项目类别:
Inducing durable, protective immune memory against malaria
诱导针对疟疾的持久、保护性免疫记忆
- 批准号:
10084807 - 财政年份:2019
- 资助金额:
$ 82.34万 - 项目类别:
Inducing durable, protective immune memory against malaria
诱导针对疟疾的持久、保护性免疫记忆
- 批准号:
10545746 - 财政年份:2019
- 资助金额:
$ 82.34万 - 项目类别:
Molecular Determinants of Sporozoite / Host Cell Interactions
子孢子/宿主细胞相互作用的分子决定因素
- 批准号:
10192640 - 财政年份:2018
- 资助金额:
$ 82.34万 - 项目类别:
Refining Mendelian genetics of malaria parasites
完善疟疾寄生虫的孟德尔遗传学
- 批准号:
10216647 - 财政年份:2017
- 资助金额:
$ 82.34万 - 项目类别:
相似国自然基金
铁锰氧化物驱动的甲烷厌氧氧化生物学机制及对人工湿地甲烷减排研究
- 批准号:52370117
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
光触发邻二酮的生物正交合成及其与靶蛋白中精氨酸选择性偶联的生物学应用
- 批准号:22377088
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
水稻土天然有机质还原偶联氨厌氧氧化过程及其微生物学机制
- 批准号:42377289
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
ecDNA驱动的MYC和INSM1协同表达在维持宫颈小细胞癌生物学特性中的作用及机制研究
- 批准号:82372672
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
塑料源DOM驱动红树林沉积物碳排放的微生物学机制
- 批准号:42306243
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Decoding Microbial Diversity in the Human Gut Microbiome
解码人类肠道微生物组中的微生物多样性
- 批准号:
10713170 - 财政年份:2023
- 资助金额:
$ 82.34万 - 项目类别:
Novel Dual-Stage Antimalarials: Machine learning prediction, validation and evolution
新型双阶段抗疟药:机器学习预测、验证和进化
- 批准号:
10742205 - 财政年份:2023
- 资助金额:
$ 82.34万 - 项目类别:
Elucidating the functions of red blood cell factors in malaria parasite invasion
阐明红细胞因子在疟原虫入侵中的功能
- 批准号:
10736484 - 财政年份:2023
- 资助金额:
$ 82.34万 - 项目类别:
Computer Vision for Malaria Microscopy: Automated Detection and Classification of Plasmodium for Basic Science and Pre-Clinical Applications
用于疟疾显微镜的计算机视觉:用于基础科学和临床前应用的疟原虫自动检测和分类
- 批准号:
10576701 - 财政年份:2023
- 资助金额:
$ 82.34万 - 项目类别:
Functional characterization of striated fiber assemblins in malaria parasites
疟疾寄生虫中横纹纤维组装体的功能特征
- 批准号:
10675782 - 财政年份:2023
- 资助金额:
$ 82.34万 - 项目类别: