How do viruses evict close relatives, and why?

病毒如何驱逐近亲，为什么？

• 批准号: 1758912
• 负责人: Feng Qu
• 金额: $ 40万
• 依托单位: Ohio State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1758912&HistoricalAwards=false
• 关键词: How; do; viruses; evict; close

Virus diseases quickly spread among host individuals because viruses are able to multiply exponentially in each of the successive hosts they invade. The fast multiplication inevitably introduces high numbers of errors in virus genetic blueprints (genomes). Left unchecked, these errors would render most of the multiplied viruses defective, thus arresting the spread of virus diseases. Conversely, natural selection favors viruses that have the capacity to control error proliferation. Once better understood, such error mitigation mechanisms could become targets of virus disease control and management. Previous research unveiled a simple, elegant mechanism used by a plant virus that minimizes multiplication errors. This mechanism operates by excluding the virus genomes produced in any given cells from additional rounds of multiplication, thereby preventing the piling-up of multiple errors in single genomes. The goals of the research are to gain a deeper understanding of this mechanism, and to determine whether this error-purging strategy is mechanistically conserved among similar viruses. Discoveries are expected to ignite intense interest in novel preventive, therapeutic, and management strategies that abolish error purging by viruses, leading to more effective control of viral diseases, which will benefit society at large. The conscious decision to enlist both graduate and undergraduate students, especially those of under-represented backgrounds, to accomplish the research contributes to the societal goal of educating high quality future scientists through integration of teaching and research. Viruses block re-infection of their host cells by closely related viruses through superinfection exclusion (SIE). SIE is strongest when the primary and superinfecting viruses are identical. How this highly specific self-rejection is achieved, and why it is conserved among diverse viruses, are key questions of this research. Use of the the plant-infecting turnip crinkle virus (TCV) allowed the discovery that p28, one of the TCV replication proteins, facilitates replication of the primary TCV, but represses replication of nearly identical superinfectors through SIE. TCV p28 was further found to coalesce into large intracellular inclusions that trapped new p28 molecules translated from superinfector genomes. Together these findings prompted the idea that the "intended" target of SIE is progenies of the primary virus because, at the time of superinfector intrusion, these progenies would far outnumber the nearly indistinguishable superinfector. This project aims to test two inter-connected hypotheses: (1) a repressive state of p28 exerts SIE in TCV-infected cells by intercepting freshly translated p28 molecules in a prion-like manner; (2) The primary function of SIE, at least for RNA viruses like TCV, is to exclude progeny genomes from re-replication, thereby minimizing random replication errors in any given progeny genomes. These hypotheses will be addressed in four objectives: (i) determine the structural characteristics of TCV p28 in vivo and in vitro; (ii) identify and characterize SIE-defective TCV mutants; (iii) characterize SIE determinants encoded by two viruses of the family Potyviridae; and (iv) determine the molecular mechanism of SIE in these Potyviridae viruses. This project strives to identify motivated students from low-income, rural families through close collaborations with a community college, and recruit them as undergraduate and graduate participants of the underlying research.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.

病毒疾病在宿主个体中迅速传播，因为病毒能够在其入侵的每个连续宿主中呈指数倍增。快速繁殖不可避免地会在病毒遗传蓝图（基因组）中引入大量错误。如果不加以控制，这些错误将使大多数繁殖的病毒出现缺陷，从而阻止病毒性疾病的传播。相反，自然选择有利于有能力控制错误扩散的病毒。一旦更好地理解，这种错误缓解机制可能成为病毒性疾病控制和管理的目标。先前的研究揭示了植物病毒使用的一种简单而优雅的机制，可以最大限度地减少繁殖错误。这种机制的运作原理是将任何给定细胞中产生的病毒基因组排除在额外的倍增轮次之外，从而防止单个基因组中多个错误的堆积。该研究的目标是更深入地了解这种机制，并确定这种错误清除策略在类似病毒中是否在机制上是保守的。预计这些发现将激发人们对新型预防、治疗和管理策略的浓厚兴趣，这些策略消除了病毒的错误清除，从而更有效地控制病毒性疾病，这将使整个社会受益。有意识地决定招募研究生和本科生，特别是那些背景不足的学生来完成研究，有助于实现通过教学和研究相结合来培养高素质未来科学家的社会目标。 病毒通过重复感染排除（SIE）来阻止密切相关的病毒对其宿主细胞的再次感染。当原发病毒和重复感染病毒相同时，SIE 最强。这种高度特异性的自我排斥是如何实现的，以及为什么它在不同的病毒中是保守的，是这项研究的关键问题。使用感染植物的芜菁皱病毒 (TCV) 发现 p28（TCV 复制蛋白之一）可促进初级 TCV 的复制，但通过 SIE 抑制几乎相同的超级感染者的复制。进一步发现 TCV p28 合并成大的细胞内包涵体，捕获从超级感染者基因组翻译的新 p28 分子。这些发现共同提出了这样一种观点，即 SIE 的“预期”目标是原发病毒的后代，因为在超级感染者入侵时，这些后代的数量将远远超过几乎无法区分的超级感染者。该项目旨在测试两个相互关联的假设：（1）p28 的抑制状态通过以类似朊病毒的方式拦截新翻译的 p28 分子，在 TCV 感染的细胞中发挥 SIE； (2) SIE的主要功能，至少对于像TCV这样的RNA病毒来说，是排除子代基因组的再复制，从而最大限度地减少任何给定子代基因组中的随机复制错误。这些假设将在四个目标中得到解决：（i）确定 TCV p28 体内和体外的结构特征； (ii) 鉴定和表征 SIE 缺陷型 TCV 突变体； (iii) 表征马铃薯病毒科两种病毒编码的 SIE 决定簇； (iv) 确定这些马铃薯病毒科病毒中 SIE 的分子机制。该项目致力于通过与社区大学的密切合作，识别来自低收入农村家庭的有积极性的学生，并招募他们作为基础研究的本科生和研究生参与者。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Translation-Independent Roles of RNA Secondary Structures within the Replication Protein Coding Region of Turnip Crinkle Virus

• DOI: 10.3390/v12030350
• 发表时间: 2020-03-01
• 期刊: VIRUSES-BASEL
• 影响因子: 4.7
• 作者: Sun, Rong;Zhang, Shaoyan;Qu, Feng
• 通讯作者: Qu, Feng

The HC-Pro cistron of Triticum mosaic virus is dispensable for systemic infection in wheat but is required for symptom phenotype and efficient genome amplification.

• DOI: 10.1016/j.virusres.2023.199277
• 发表时间: 2024-01-02
• 期刊: VIRUS RESEARCH
• 影响因子: 5
• 作者: Tatineni, Satyanarayana;Alexander, Jeffrey;Kovacs, Frank
• 通讯作者: Kovacs, Frank

Replication-Dependent Biogenesis of Turnip Crinkle Virus Long Noncoding RNAs

• DOI: 10.1128/jvi.00169-21
• 发表时间: 2021-05
• 期刊: Journal of Virology
• 影响因子: 5.4
• 作者: Shaoyan Zhang;Rong Sun;Camila Perdoncini Carvalho;Junping Han;Limin Zheng;F. Qu

Natural Selection, Intracellular Bottlenecks of Virus Populations, and Viral Superinfection Exclusion

• DOI: 10.1146/annurev-virology-100520-114758
• 发表时间: 2022-01-01
• 期刊: ANNUAL REVIEW OF VIROLOGY
• 影响因子: 11.3
• 作者: Carvalho, Camila Perdoncini;Ren, Ruifan;Qu, Feng
• 通讯作者: Qu, Feng

Repression of turnip crinkle virus replication by its replication protein p88

• DOI: 10.1016/j.virol.2018.10.024
• 发表时间: 2019-01-02
• 期刊: VIROLOGY
• 影响因子: 3.7
• 作者: Zhang, Shaoyan;Sun, Rong;Qu, Feng
• 通讯作者: Qu, Feng