Local translation and viral infection in the airway epithelium

气道上皮的局部翻译和病毒感染

基本信息

项目摘要

Project Summary - Abstract Multiciliated cells (MCCs) are key components of the airway epithelium playing a major role in mucociliary clearance, the first line of lung defense against inhaled pathogens. MCCs are well-known targets of viral pathogens, including influenza A, SARS-COVID2 and respiratory syncytial virus (RSV), often resulting in severe respiratory conditions with long-term sequelae and morbidity. Still there are major gaps of knowledge on the mechanisms by which these pathogens trigger airway disease. MCCs require production and apical localization of a large number of proteins essential for the assembly of hundreds of cilia per cell during multiciliogenesis. The mechanisms that allow efficient production and local translation of these proteins in MCCs are still poorly understood. There is evidence that during viral infection, the host’s cellular translation machinery is hijacked to produce viral proteins for replication. How local translation is established in MCCs and targeted in viral infection will be studied in this proposal. Our preliminary studies revealed a striking expression of translation initiation factors (eIFs), ribosomal proteins and nascent polypeptides colocalized with miRNAs, Trinucleotide repeat- containing 6a (TNRC6a) and Argonaute 2 (AGO2) in immature MCCs undergoing multiciliogenesis. These signals were concentrated in not yet reported apical cytoplasmic granules, which we named as Localized Translation granules (LT granules). Surprisingly, unlike other granules traditionally associated with miRNA function, no enzymes required for mRNA degradation were detected in LT granules. Instead, LT granules were highly active sites of protein translation. Notably, disrupting Tnrc6a expression, disturbed local translation and resulted in defective multicilia formation, a phenotype we also observed in RSV-infected MCCs. Here we will test the hypotheses that i) components of the miRNA pathway recruit subsets of mRNAs and the translation machinery to LT granules for local efficient large-scale protein synthesis during MCC differentiation; ii) disruption of this local translation program is a key determinant in the pathogenesis of RSV infection. Thus, we propose to identify mechanisms that target mRNAs (Aim 1) and recruit the translation machinery (Aim 2) to LT granules in MCCs, and determine how RSV disrupts these mechanisms to infect the human airway epithelium (Aim 3). The knowledge generated from these studies will significantly advance our understanding of the mechanisms of local translation in multiciliogenesis and the pathogenesis of RSV infection in the respiratory tract. RELEVANCE TO PUBLIC HEALTH: Multiciliated cells (MCCs) are crucial components of the defense mechanisms of the lung. Viral infections in the immature epithelium of conducting airways can have devastating effects in infants or adults with compromised respiratory function. Novel information generated from these studies will advance our understanding of how proper ciliogenesis is regulated, and how viral infections, such as RSV disrupt cilia formation in immature respiratory tract.
项目摘要-摘要

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)

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Wellington V. Cardoso其他文献

420 INTEGRATING HPSC-DERIVED 3D ORGANOIDS AND MOUSE GENETICS TO DEFINE A NOVEL ROLE OF YAP IN ESOPHAGEAL DEVELOPMENT
  • DOI:
    10.1016/s0016-5085(20)30885-4
  • 发表时间:
    2020-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Dominique Bailey;Yongchun Zhang;Benjamin J. van Soldt;Ming Jiang;Wellington V. Cardoso;Jianwen Que
  • 通讯作者:
    Jianwen Que
Morphogenesis and regeneration share a conserved core transition cell state program that controls lung epithelial cell fate
形态发生和再生共享一个保守的核心过渡细胞状态程序,该程序控制肺上皮细胞的命运。
  • DOI:
    10.1016/j.devcel.2024.11.017
  • 发表时间:
    2025-03-24
  • 期刊:
  • 影响因子:
    8.700
  • 作者:
    Xiangyi Ke;Benjamin van Soldt;Lukas Vlahos;Yizhuo Zhou;Jun Qian;Joel George;Claudia Capdevila;Ian Glass;Kelley Yan;Andrea Califano;Wellington V. Cardoso
  • 通讯作者:
    Wellington V. Cardoso

Wellington V. Cardoso的其他文献

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{{ truncateString('Wellington V. Cardoso', 18)}}的其他基金

Regulation of Progenitor Cell Plasticity in Lung Development and Disease-Repair
肺发育和疾病修复中祖细胞可塑性的调节
  • 批准号:
    10574208
  • 财政年份:
    2023
  • 资助金额:
    $ 65.23万
  • 项目类别:
Mechanisms Controlling Expansion and Lineage Specification of Airway Progenitors in Development and Disease
发育和疾病中气道祖细胞扩张和谱系规范的控制机制
  • 批准号:
    9898430
  • 财政年份:
    2017
  • 资助金额:
    $ 65.23万
  • 项目类别:
Mechanisms Controlling Expansion and Lineage Specification of Airway Progenitors in Development and Disease
发育和疾病中气道祖细胞扩张和谱系规范的控制机制
  • 批准号:
    10360447
  • 财政年份:
    2017
  • 资助金额:
    $ 65.23万
  • 项目类别:
Mechanisms Controlling Expansion and Lineage Specification of Airway Progenitors in Development and Disease
发育和疾病中气道祖细胞扩张和谱系规范的控制机制
  • 批准号:
    10225231
  • 财政年份:
    2017
  • 资助金额:
    $ 65.23万
  • 项目类别:
Mechanisms Controlling Expansion and Lineage Specification of Airway Progenitors in Development and Disease
发育和疾病中气道祖细胞扩张和谱系规范的控制机制
  • 批准号:
    9244583
  • 财政年份:
    2017
  • 资助金额:
    $ 65.23万
  • 项目类别:
Mechanisms Controlling Expansion and Lineage Specification of Airway Progenitors in Development and Disease
发育和疾病中气道祖细胞扩张和谱系规范的控制机制
  • 批准号:
    10642657
  • 财政年份:
    2017
  • 资助金额:
    $ 65.23万
  • 项目类别:
The Trinucleotide Repeat Containing 6a-Mediated miRNA Activities in the Ciliogenesis of Airway Epithelium
含有 6a 的三核苷酸重复介导的 miRNA 在气道上皮纤毛发生中的活性
  • 批准号:
    9196391
  • 财政年份:
    2016
  • 资助金额:
    $ 65.23万
  • 项目类别:
The Trinucleotide Repeat Containing 6a-Mediated miRNA Activities in the Ciliogenesis of Airway Epithelium
含有 6a 的三核苷酸重复介导的 miRNA 在气道上皮纤毛发生中的活性
  • 批准号:
    9055981
  • 财政年份:
    2016
  • 资助金额:
    $ 65.23万
  • 项目类别:
REGULATION OF THE CILIATED CELL PROGRAM IN AIRWAY PROGENITORS
气道祖细胞中纤毛细胞程序的调节
  • 批准号:
    8710697
  • 财政年份:
    2014
  • 资助金额:
    $ 65.23万
  • 项目类别:
REGULATION OF AIRWAY PROGENITOR CELL FATE IN DEVELOPMENT AND REGENERATION
气道祖细胞发育和再生命运的调节
  • 批准号:
    8186701
  • 财政年份:
    2011
  • 资助金额:
    $ 65.23万
  • 项目类别:

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