How do viruses evict close relatives, and why?

病毒疾病在宿主个体中迅速传播，因为病毒能够在它们入侵的每个连续宿主中指数级地繁殖。快速的繁殖不可避免地在病毒基因蓝图(基因组)中引入了大量的错误。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。一旦更好地了解，这种错误缓解机制可能成为病毒疾病控制和管理的目标。之前的研究揭示了一种植物病毒使用的简单、优雅的机制，它可以最大限度地减少繁殖错误。这一机制的运作方式是将在任何给定细胞中产生的病毒基因组排除在额外的几轮增殖之外，从而防止在单个基因组中堆积多个错误。这项研究的目标是更深入地了解这一机制，并确定这种错误清除策略是否在类似病毒中具有机械保守性。预计这些发现将激发人们对新的预防、治疗和管理策略的浓厚兴趣，这些策略将消除病毒清除错误，导致更有效地控制病毒疾病，这将造福整个社会。有意识地决定招募研究生和本科生，特别是那些背景不够充分的人来完成研究，这有助于通过教学和研究的结合培养高质量的未来科学家的社会目标。病毒通过重叠感染排斥(SIE)阻止密切相关病毒对宿主细胞的再次感染。当主要感染病毒和超级感染病毒相同时，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。利用侵染植物的芜菁皱纹病毒(TCV)可以发现，P28是TCV的复制蛋白之一，它促进了初级TCV的复制，但通过SIE抑制了几乎相同的超级病毒的复制。TCV p28进一步被发现结合成大的细胞内包涵体，捕获从超级感染者基因组翻译的新的p28分子。总而言之，这些发现促使人们产生这样的想法，即SIE的“预定”目标是主要病毒的后代，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。本项目旨在检验两个相互关联的假说：(1)p28的抑制状态通过以类似普恩的方式截取新翻译的p28分子，在TCV感染的细胞中发挥SIE作用；(2)SIE的主要功能，至少对TCV等RNA病毒来说，是将后代基因组排除在重新复制之外，从而将任何给定的子代基因组中的随机复制错误降至最低。这些假说将从四个方面进行研究：(1)确定TCV p28在体内和体外的结构特征；(2)鉴定和鉴定缺失SIE的TCV突变体；(3)鉴定由马铃薯Y病毒科两种病毒编码的SIE决定簇；(4)确定这些马铃薯Y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，从低收入、农村家庭中寻找有动力的学生，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优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.