Uncovering poxvirus proteins involved in regulating the IMV to EV transition

描述（由申请人提供）：痘病毒包括一个能够感染和引起人类疾病的DNA病毒大家族。虽然最臭名昭著的天花病毒，天花的病原体，已经从自然感染中被根除，但人们仍然担心在生物攻击期间秘密释放。此外，猴痘和其他家族成员引起了人们对能够引起流行病的动物传染病的关注。痘病毒产生两种感染形式，细胞内成熟病毒（IMV）和细胞外病毒（EV）。虽然IMV占后代的大部分，但WV是有效的细胞间传播和全身感染所必需的。EV是由IMV的胞内包膜形成的。它们的形成发生在感染细胞的细胞质中，已知只有8种由病毒编码的蛋白质是WV形式所特有的。该项目的长期目标是了解正痘病毒形成、运输和释放感染性WV的分子机制。这个应用程序的直接目标是理解是什么调节了从IMV到EV的转变。我们的假设是，病毒编码了一个分子开关，该开关逐渐积累到足够的数量以阻止EV的形成，从而允许IMV的积累。我们的具体目标是；1)研究IMV-EV转化的时间关系；2)对参与EV形成/抑制的蛋白进行基因筛选。这一结果将进一步揭示痘病毒调控两种传染性病毒粒子形成的分子机制，并使我们更好地了解痘病毒的形态发生和输出。

DESCRIPTION (provided by applicant): Poxviruses include a large family of DNA viruses capable of infecting and causing disease in humans. While the most notorious member variola, the causative agent of smallpox, was eradicated from natural infection, there are still concerns about a clandestine release during a biological attack. In addition, monkeypox and other members of the family have raised concern about epizootic infections that are capable of causing epidemic. Poxviruses produce two infectious forms, intracellular mature virus (IMV) and extracellular virus (EV). While IMV make up the majority of progeny, WV is required for efficient cell-to-cell spread and systemic infection. EV are formed by the intracellular envelopment of IMV. Their formation occurs in the cytoplasm of infected cells and only 8 proteins encoded by the virus are known to be unique to the WV form. The long-term goal of this project is to understand the molecular mechanisms employed by orthopoxoviruses to form, transport, and release infectious WV. The immediate goal of this application is to understand what regulates the transition of IMV to EV. Our hypothesis is that the virus encodes a molecular switch that gradually accumulates to sufficient quantities to block the formation of EV thus allowing the accumulation of IMV. Our specific aims are; 1) Investigation of the temporal relationship of the IMV-EV transition, 2) Perform a genetic screen for proteins involved in EV formation/inhibition. The results obtained will provide greater insight into the molecular mechanism poxviruses use to regulate the formation of the two forms of infectious virions and give us a better understanding of poxvirus morphogenesis and egress. PUBLIC HEALTH RELEVANCE: Even though natural occurring smallpox was eradicated, concern for orthopoxviruses, ranging from a clandestine release of smallpox to outbreaks of epizootic infections such as monkeypox, still exist. Understanding the biology of poxviruses is still a priority not only for preventing epidemics but also for understanding basic mechanisms of biology. The results from this study will provide new insights into poxvirus infections, which will provide new targets for antivirals and treatments against their infections.