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RUI: Transcriptional regulation of host-pathogen viral symbiosis at single-cell resolution

RUI：单细胞分辨率下宿主-病原体病毒共生的转录调控

基本信息

批准号：
2110223
负责人：
JJ Miranda
金额：
$ 41.27万
依托单位：
Barnard College
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2110223&HistoricalAwards=false
关键词：
RUI Transcriptional regulation host pathogen

项目摘要

Many viruses infect hosts for a lifetime. In order to do so, viruses must balance opposing needs that affect timing of the life cycle. On one hand, active replication is required to make more copies and propagate. On the other hand, inactive dormancy is required to avoid host detection and immune responses that could clear the virus. These oscillations in viral growth involve changes in viral gene expression. The infected host cell counters with subsequent changes in its own gene expression to perturb the viral life cycle. This competition between host and pathogen has been well studied at the population level. Emerging data in the field, however, argues that individual viruses in a population do not act in unison. To balance the risk of active replication with the safety of inactive dormancy, subpopulations may express different genes. This project aims to study how viruses generate diverse subpopulations during both active replication and inactivate dormancy. Data obtained by a research team will then be analyzed by an undergraduate computational biology class specifically designed to write code for this project. Barnard College, a liberal arts school for women, will support this effort through collaboration with established program cohorts that recruit underrepresented minorities. The integrated goals of the project are to advance knowledge of fundamental questions at the interface of virology and computer science while simultaneously increasing participation of underrepresented women in computational biology.Human herpesvirus-8 (HHV-8) is a double stranded DNA virus that persists in the host by establishing a lifelong symbiotic infection. Persistence over years strongly depends on the ability of the virus to shut down transcription to a quiescent latent state not detectable by the host. Equally important is also the ability to spontaneously replicate in response to cellular stress and generate new virions to replenish a depleted reservoir. While much work has been done to understand the molecular basis of this lytic reactivation in a bulk population, studies at single-cell resolution have been lacking. Preliminary data demonstrates that HHV-8 populations display clear heterogeneity with multiple subpopulations. HHV-8 reactivation is also enriched in one specific subpopulation with a distinct host transcriptional signature. Specific Aim 1 will test the effect of identified candidate host genes on HHV-8 reactivation. Specific Aim 2 will identify which subpopulations respond most readily to different stimuli of reactivation. Both aims build on a wide body of literature in the microbial world demonstrating a transcriptional basis to bet-hedging within a heterogeneous population. The sum of experiments will advance our knowledge of the single-cell transcriptomes that control HHV-8 reactivation. The Department of Biology at Barnard College is establishing a new major in computational biology. This project will specifically contribute through the establishment of a new course-based undergraduate research experience, “Computational ViroSystOmics,” based on the experiments performed. The course will integrate strategies mindful of pedagogical studies of gender in computer science.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

许多病毒感染宿主一辈子。为了做到这一点，病毒必须平衡影响生命周期时间的对立需求。一方面，主动复制需要制作更多的副本和传播。另一方面，需要非活性休眠以避免宿主检测和可能清除病毒的免疫反应。病毒生长中的这些振荡涉及病毒基因表达的变化。受感染的宿主细胞随后会改变自身的基因表达，从而扰乱病毒的生命周期。宿主和病原体之间的这种竞争已经在种群水平上得到了很好的研究。然而，该领域的新数据认为，群体中的单个病毒并不一致。为了平衡活跃复制的风险和非活跃休眠的安全性，亚群可能表达不同的基因。该项目旨在研究病毒如何在活跃复制和休眠期间产生不同的亚群。研究团队获得的数据将由专门为该项目编写代码的本科计算生物学课程进行分析。巴纳德学院是一所女子文科学校，将通过与招收代表性不足的少数民族的既定项目群体合作来支持这一努力。该项目的综合目标是提高对病毒学和计算机科学界面上的基本问题的认识，同时增加代表性不足的妇女对计算生物学的参与。人类疱疹病毒-8（HHV-8）是一种双链DNA病毒，通过建立终身共生感染而在宿主中持续存在。持续数年在很大程度上取决于病毒将转录关闭到宿主无法检测到的静止潜伏状态的能力。同样重要的是响应细胞应激而自发复制并产生新病毒体以补充耗尽的储存库的能力。虽然已经做了大量的工作，以了解这种裂解在一个大的人口重新激活的分子基础，在单细胞分辨率的研究一直缺乏。初步数据表明，HHV-8群体显示出明显的异质性，具有多个亚群。HHV-8再活化也富集在一个具有不同宿主转录特征的特定亚群中。具体目标1将测试已识别的候选宿主基因对HHV-8再激活的影响。具体目标2将确定哪些亚群最容易对不同的再激活刺激作出反应。这两个目标都建立在微生物世界中的大量文献的基础上，这些文献证明了异质群体中赌注对冲的转录基础。这些实验的总结将推进我们对控制HHV-8再激活的单细胞转录组的认识。巴纳德学院生物系正在建立一个新的计算生物学专业。该项目将通过建立一个新的基于课程的本科生研究经验，“计算病毒系统组学”，根据所进行的实验作出具体贡献。该奖项反映了国家科学基金会的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。