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

基本信息

  • 批准号:
    10736484
  • 负责人:
  • 金额:
    $ 75.9万
  • 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:
    2023-07-01 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ ABSTRACT Malaria is a leading cause of morbidity and mortality globally, responsible for the deaths of hundreds of thousands of individuals per year, primarily children and pregnant women. Effective control is hampered by the lack of a vaccine and continually emerging drug resistance. Most cases of severe malaria are caused by Plasmodium falciparum, which is an obligate intracellular parasite of human red blood cells (RBCs). Therefore, critical host factors may provide an untapped source of new therapeutic targets. Red blood cell invasion is a complex process that involves interactions between several parasite ligands and host receptors, but there remains a fundamental gap in knowledge regarding the functional role(s) of RBC host factors for P. falciparum. This gap in our knowledge is, in part, due to RBCs being terminally differentiated and lacking DNA, thereby precluding conventional genetic experimentation. To surmount this roadblock, we have recently developed CRISPR-Cas9-based methods to generate null mutants in primary human hematopoietic stem cells and efficiently differentiate them ex-vivo to mature cultured RBCs (cRBCs), opening new opportunities for functional analysis of these important cells. Our objective in this proposal is to comprehensively determine the specific roles and functions of two novel RBC host factors required for P. falciparum invasion, CD44 and CD55, which were recently identified from a forward genetic screen. Our central hypothesis, supported by strong preliminary data, is that these critical surface receptors play distinct yet synergistic roles to facilitate P. falciparum invasion through their interactions with parasite ligands and subsequent signaling to the host cell. In the first aim, we will determine the precise steps involving CD44 and CD55 in P. falciparum invasion of human RBCs using live cell imaging and advanced microscopy. In the second aim, avidity-based and proximity labeling proteomic approaches will be used to identify P. falciparum and RBC binding partners for CD44 and CD55. In the final aim, we will define host RBC signaling pathways activated by P. falciparum invasion, and test their dependence on CD44 and CD55. Together, these studies will generate a comparative understanding of the mechanistic roles of two novel host factors crucial for P. falciparum invasion. In addition to revealing new insights into the fundamental cell biology of Plasmodium invasion and human RBCs, this work will stimulate new therapeutic and vaccine approaches to treat one of the most important infectious diseases of humankind.
项目总结/摘要 疟疾是全球发病率和死亡率的主要原因,造成数百人死亡, 每年有数千人死亡,主要是儿童和孕妇。有效控制受到以下因素的阻碍: 缺乏疫苗和不断出现的耐药性。大多数严重疟疾病例是由 恶性疟原虫是一种专性的人体红细胞(RBC)内寄生虫。因此,我们认为, 关键的宿主因素可以提供新的治疗靶点的未开发的来源。红细胞入侵是一种 一个复杂的过程,涉及几个寄生虫配体和宿主受体之间的相互作用,但 关于红细胞宿主因子对恶性疟原虫的功能作用的认识仍然存在根本性的空白。 我们知识中的这一差距部分是由于RBC是终末分化的并且缺乏DNA,从而 排除了传统的基因实验。为了克服这一障碍,我们最近开发了 在原代人造血干细胞中产生无效突变体的基于CRISPR-Cas9的方法和 有效地将它们离体分化为成熟的培养红细胞(cRBC),为功能性红细胞(cRBC)提供了新的机会。 分析这些重要的细胞。我们在这一建议中的目标是全面确定 恶性疟原虫侵袭所需的两种新的红细胞宿主因子CD 44和CD 55的作用和功能, 是最近通过遗传筛查发现的我们的中心假设得到了初步的有力支持, 这些重要的表面受体在促进恶性疟原虫侵袭方面发挥着独特而协同的作用 通过它们与寄生虫配体的相互作用和随后向宿主细胞的信号传导。在第一个目标中,我们将 使用活细胞测定恶性疟原虫侵入人红细胞中涉及CD 44和CD 55的精确步骤 成像和先进的显微镜。在第二个目标中,基于亲合力和邻近标记的蛋白质组学 方法将用于鉴定恶性疟原虫和RBC的CD 44和CD 55结合配偶体。在最后的目标中, 我们将定义恶性疟原虫入侵激活的宿主RBC信号通路,并测试它们对 CD 44和CD 55。总之,这些研究将产生一个比较理解的机械作用, 两个新的宿主因子对恶性疟原虫入侵至关重要。除了揭示对基本的新见解, 疟原虫入侵和人类红细胞的细胞生物学,这项工作将刺激新的治疗和疫苗 治疗人类最重要的传染病之一的方法。

项目成果

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Elizabeth S. Egan其他文献

Coupling cryo-electron tomography with mixed-scale dense neural networks reveals re-organization of the invasion machinery of Toxoplasma gondii upon ionophore-stimulation
冷冻电子断层扫描与混合尺度密集神经网络的耦合揭示了弓形虫入侵机制在离子载体刺激下的重组
  • DOI:
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    L. Segev;P. Dahlberg;Stella Y. Sun;Daniël M. Pelt;Chi Yong Kim;Elizabeth S. Egan;J. Sethian;Wah Chiu;J. Boothroyd
  • 通讯作者:
    J. Boothroyd
Malaria parasite fitness in healthy human red cells is driven by common host variation
健康人类红细胞中疟原虫的适应性是由常见的宿主变异驱动的
  • DOI:
    10.1101/2020.10.08.332494
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    E. Ebel;Kuypers Fa;C. H. Lin;D. Petrov;Elizabeth S. Egan
  • 通讯作者:
    Elizabeth S. Egan
A common polymorphism in the druggable ion channel PIEZO1 is associated with protection from severe malaria
可药物离子通道 PIEZO1 中常见的多态性与预防严重疟疾相关
  • DOI:
    10.1101/691253
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    C. Nguetse;N. Purington;B. Shakya;E. Ebel;P. Kremsner;T. Velavan;Elizabeth S. Egan
  • 通讯作者:
    Elizabeth S. Egan
Investigating a Novel Erythrocyte Kinase and Its Impact on <em>Plasmodium Falciparum</em> Infection
  • DOI:
    10.1182/blood-2024-211105
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Daniel J Navarrete;Chi Yong Kim;Mario Gonzalez;Barbara Baro;Christian Doerig;Shao-En Ong;Martin Golkowski;Elizabeth S. Egan
  • 通讯作者:
    Elizabeth S. Egan
Investigating a Novel Erythrocyte Kinase and Its Impact on emPlasmodium Falciparum/em Infection
研究一种新型红细胞激酶及其对恶性疟原虫感染的影响
  • DOI:
    10.1182/blood-2024-211105
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
    23.100
  • 作者:
    Daniel J Navarrete;Chi Yong Kim;Mario Gonzalez;Barbara Baro;Christian Doerig;Shao-En Ong;Martin Golkowski;Elizabeth S. Egan
  • 通讯作者:
    Elizabeth S. Egan

Elizabeth S. Egan的其他文献

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{{ truncateString('Elizabeth S. Egan', 18)}}的其他基金

Identifying critical erythrocyte host factors for Plasmodium falciparum malaria
确定恶性疟原虫疟疾的关键红细胞宿主因子
  • 批准号:
    9167283
  • 财政年份:
    2016
  • 资助金额:
    $ 75.9万
  • 项目类别:
Functional genomic analysis of host determinants of malaria infection
疟疾感染宿主决定因素的功能基因组分析
  • 批准号:
    8666714
  • 财政年份:
    2013
  • 资助金额:
    $ 75.9万
  • 项目类别:
Functional genomic analysis of host determinants of malaria infection
疟疾感染宿主决定因素的功能基因组分析
  • 批准号:
    8581728
  • 财政年份:
    2013
  • 资助金额:
    $ 75.9万
  • 项目类别:
Functional genomic analysis of host determinants of malaria infection
疟疾感染宿主决定因素的功能基因组分析
  • 批准号:
    9171958
  • 财政年份:
    2013
  • 资助金额:
    $ 75.9万
  • 项目类别:

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开发疟原虫乙酰辅酶A合成酶抑制剂作为新型多级抗疟药
  • 批准号:
    MR/X030202/1
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    2023
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开发针对寄生虫辅酶 A 生物合成和利用的新型先导抗疟药。
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重新利用抗疟药治疗 NTM 感染
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