Uncovering poxvirus proteins involved in regulating the IMV to EV transition

描述（由申请方提供）：痘病毒包括能够感染人类并引起人类疾病的DNA病毒大家族。虽然最臭名昭著的成员天花，天花的病原体，从自然感染中被根除，但仍然有人担心在生物攻击期间秘密释放。此外，猴痘和该家族的其他成员引起了人们对能够引起流行病的动物流行病感染的关注。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在细胞内增殖形成的。它们的形成发生在感染细胞的细胞质中，已知该病毒编码的蛋白质中只有8种是WV形式所独有的。该项目的长期目标是了解正痘病毒形成、运输和释放传染性WV的分子机制。本申请的直接目标是了解是什么调节了IMV到EV的转变。我们的假设是，病毒编码一个分子开关，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转变的时间关系，2）对涉及EV形成/抑制的蛋白质进行遗传筛选。所获得的结果将提供更深入的了解痘病毒用于调节两种形式的感染性病毒体的形成的分子机制，并使我们更好地了解痘病毒的形态发生和出口。 公共卫生相关性：尽管自然发生的天花已被根除，但对正痘病毒的担忧，从天花的秘密释放到动物流行病感染如猴痘的爆发，仍然存在。了解痘病毒的生物学仍然是一个优先事项，不仅是为了预防流行病，而且是为了了解生物学的基本机制。这项研究的结果将为痘病毒感染提供新的见解， 为抗病毒药物和治疗提供了新的靶点。

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.