Regulation of DNA Damage and Innate Immunity During the Productive Phase of the HPV Life Cycle

HPV 生命周期生产阶段 DNA 损伤和先天免疫的调节

基本信息

  • 批准号:
    10392849
  • 负责人:
  • 金额:
    $ 19.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-15 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

The productive phase of the HPV life cycle is restricted to the uppermost layer of the epithelium in cells that have normally exited the cell cycle. The E7 protein alters cell cycle regulation, pushing differentiating cells back into the cell cycle to allow for viral genome amplification to 1000s of copies per cell and virion production. Cell cycle deregulation by E7 leads to genomic instability that is a driving force in cancer development. Our long-term goal is to understand mechanisms that regulate productive viral replication, which is important to understanding how HPV causes cancer. While caspase activation is typically viewed as an anti-viral response, HPV requires low level activation of caspases belonging to the mitochondrial pathway of apoptosis for productive replication. In this apoptotic pathway, cell death is initiated by mitochondrial membrane permeabilization (MOMP), which normally induces rapid cell death. Interestingly, HPV-induced caspase activation is not accompanied by morphological features of apoptosis, suggesting that HPV may restrain MOMP to limit caspase activity. How HPV is able to take advantage of pro-viral caspase functions by blocking apoptosis is currently unclear. Caspase cleavage of the HPV E1 helicase is required for productive replication, indicating that caspases directly regulate productive replication. However, caspase activation induces DNA damage and activates DNA damage response (DDR) pathways through JNK1/2, and we have found JNK1/2 activation increases upon differentiation. While the importance of DDR pathways (e.g. ATM and ATR) in driving productive replication is well-established, the contribution of caspase activity to DDR regulation is unknown. In the absence of apoptotic caspase activity, cytosolic release of mtDNA by MOMP is sensed by the cGAS-STING pathway, leading to induction of Type I Interferons (IFN). Intriguingly, we have found that apoptotic caspase activity is necessary to block a Type I as well as Type III IFN response upon differentiation. These results indicate that caspase activity indirectly supports productive replication through effects on host cell processes in a non-lethal manner. We hypothesize that HPV exploits non-apoptotic functions of caspases upon epithelial differentiation to facilitate the productive phase of the viral life cycle. In Aim 1, we will determine if HPV induces limited caspase activation and DNA damage through minority MOMP by using innovative techniques to monitor MOMP on a single cell level; by determining if caspase activity is non-lethal in differentiating cells; and by examining the effect of caspase inhibition on DNA damage and DDR activation. In Aim 2, we will determine how HPV uses caspase activity to block the IFN response upon differentiation by examining a role for MOMP and mtDNA release in stimulating IFN production upon caspase inhibition, and by determining if caspase activity blocks the cGAS-STING DNA sensing pathway. Completion of these studies is expected to determine how caspase activity contributes to productive viral replication as well as offer insight into mechanisms of viral persistence and genomic instability. These will represent fundamental new insight into how DNA virus infection is regulated by apoptotic caspases.
HPV生命周期的生产阶段仅限于正常退出细胞周期的细胞上皮的最上层。E7蛋白改变细胞周期调节,将正在分化的细胞推回到细胞周期,使病毒基因组扩增到每个细胞1000个拷贝,并产生病毒粒子。E7细胞周期失调导致基因组不稳定,这是癌症发展的驱动力。我们的长期目标是了解调节多产病毒复制的机制,这对了解HPV如何导致癌症很重要。虽然caspase激活通常被视为抗病毒反应,但HPV需要属于凋亡线粒体途径的低水平caspase激活才能进行生产性复制。在这种凋亡途径中,细胞死亡是由线粒体膜透性(MOMP)引发的,它通常诱导细胞快速死亡。有趣的是,HPV诱导的caspase激活不伴有凋亡的形态学特征,这表明HPV可能抑制MOMP以限制caspase活性。目前尚不清楚HPV是如何通过阻断细胞凋亡来利用前病毒半胱天冬酶的功能的。HPV E1解旋酶的Caspase裂解是高效复制所必需的,这表明Caspase直接调节高效复制。然而,caspase的激活通过JNK1/2诱导DNA损伤并激活DNA损伤反应(DDR)途径,我们发现JNK1/2的激活随着分化而增加。虽然DDR途径(如ATM和ATR)在驱动生产性复制中的重要性已得到证实,但半胱天冬酶活性对DDR调控的贡献尚不清楚。在缺乏凋亡caspase活性的情况下,MOMP通过cGAS-STING途径感知细胞内mtDNA的释放,从而诱导I型干扰素(IFN)的产生。有趣的是,我们发现凋亡的caspase活性是阻断I型和III型IFN分化反应所必需的。这些结果表明,caspase活性通过非致死方式影响宿主细胞过程间接支持生产性复制。我们假设HPV利用半胱天酶在上皮分化中的非凋亡功能来促进病毒生命周期的生产阶段。在Aim 1中,我们将通过使用创新技术在单细胞水平上监测MOMP,确定HPV是否通过少数MOMP诱导有限的caspase激活和DNA损伤;通过确定半胱天冬酶活性在分化细胞中是否非致死性;并通过检测caspase抑制对DNA损伤和DDR激活的影响。在Aim 2中,我们将通过检测MOMP和mtDNA释放在caspase抑制下刺激IFN产生中的作用,以及确定caspase活性是否阻断cGAS-STING DNA传感途径,来确定HPV如何利用caspase活性来阻断分化时的IFN反应。这些研究的完成有望确定半胱天冬酶活性如何促进多产的病毒复制,并为病毒持久性和基因组不稳定性的机制提供见解。这些将代表对DNA病毒感染如何由凋亡半胱天冬酶调节的基本新见解。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Regulation of the Innate Immune Response during the Human Papillomavirus Life Cycle.
  • DOI:
    10.3390/v14081797
  • 发表时间:
    2022-08-17
  • 期刊:
  • 影响因子:
    0
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CARY A MOODY其他文献

CARY A MOODY的其他文献

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{{ truncateString('CARY A MOODY', 18)}}的其他基金

Interplay between the cellular DNA damage response and the HPV life cycle
细胞 DNA 损伤反应与 HPV 生命周期之间的相互作用
  • 批准号:
    10734394
  • 财政年份:
    2023
  • 资助金额:
    $ 19.44万
  • 项目类别:
Epigenetic Regulation During the HPV Life Cycle
HPV 生命周期中的表观遗传调控
  • 批准号:
    10295782
  • 财政年份:
    2018
  • 资助金额:
    $ 19.44万
  • 项目类别:
Epigenetic Regulation During the HPV Life Cycle
HPV 生命周期中的表观遗传调控
  • 批准号:
    10053334
  • 财政年份:
    2018
  • 资助金额:
    $ 19.44万
  • 项目类别:
Epigenetic Regulation During the HPV Life Cycle
HPV 生命周期中的表观遗传调控
  • 批准号:
    10520010
  • 财政年份:
    2018
  • 资助金额:
    $ 19.44万
  • 项目类别:
Regulation of human papillomavirus replication by the DNA damage response
DNA损伤反应调节人乳头瘤病毒复制
  • 批准号:
    9325478
  • 财政年份:
    2014
  • 资助金额:
    $ 19.44万
  • 项目类别:
Regulation of human papillomavirus replication by the DNA damage response
DNA损伤反应调节人乳头瘤病毒复制
  • 批准号:
    8926368
  • 财政年份:
    2014
  • 资助金额:
    $ 19.44万
  • 项目类别:
Regulation of human papillomavirus replication by the DNA damage response
DNA损伤反应调节人乳头瘤病毒复制
  • 批准号:
    8759078
  • 财政年份:
    2014
  • 资助金额:
    $ 19.44万
  • 项目类别:
The Role of Caspase Activation in the Differentiation-Dependent Life Cycle of HPV
Caspase 激活在 HPV 分化依赖性生命周期中的作用
  • 批准号:
    7574657
  • 财政年份:
    2008
  • 资助金额:
    $ 19.44万
  • 项目类别:
The Role of Caspase Activation in the Differentiation-Dependent Life Cycle of HPV
Caspase 激活在 HPV 分化依赖性生命周期中的作用
  • 批准号:
    8122505
  • 财政年份:
    2008
  • 资助金额:
    $ 19.44万
  • 项目类别:
The Role of Caspase Activation in the Differentiation-Dependent Life Cycle of HPV
Caspase 激活在 HPV 分化依赖性生命周期中的作用
  • 批准号:
    8307447
  • 财政年份:
    2008
  • 资助金额:
    $ 19.44万
  • 项目类别:

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