Poxvirus host interactions, pathogenesis and immunity

痘病毒由一个复杂的DNA病毒大家族组成，这些病毒有脊椎动物和无脊椎动物的宿主。天花病毒和传染性软疣病毒是人类特有的病原体。在天花被根除之前，天花病毒一直是天花的原因，但由于可能使用生物武器，人们仍然担心天花病毒。传染性软骨病病毒会导致免疫能力正常的婴儿的良性皮肤损害，以及免疫缺陷的成年人的一种更严重和更广泛的疾病。此外，几种动物痘病毒可以作为人畜共患病传播给人类。其中最严重的是猴痘，估计人类死亡率为1%至10%。痘病毒表达大量与毒力有关的宿主免疫逃避基因。本项目的目的是增加我们对痘病毒宿主相互作用、发病机制和对痘病毒免疫的基础的了解。进行了人类全基因组RNAi筛选，以确定影响痘病毒复制的宿主因素。 在过去的一年里，我们利用了235个可用的正痘病毒(ORPV)独特的完整基因组序列，并重新注释了每个基因的大约200个基因，以提供第一个统一的基因命名法。我们重点研究了大约100个辅助基因，预测了未知基因的功能，并重建了它们在ORPV进化过程中的得失历史。大多数辅助基因是在脊索痘病毒的ORPV起源之前的三个主要波中获得的。ORPV本身的进化是由基因丢失主导的，在ORPV的每个主要群体的碱基上都有许多基因丢失。经常或很少同时丢失的一对ORPV辅助基因的检测 在ORPV进化期间，允许预测不同类型的功能相互作用。

Poxviruses comprise a large family of complex DNA viruses that have vertebrate and invertebrate hosts. Two poxviruses, variola virus and molluscum contagiosum virus, are specific human pathogens. Variola virus was the cause of smallpox until the latter was eradicated but is still feared because of potential use a biological weapon. Molluscum contagiosum virus causes benign skin lesions in immunocompetent infants and a more severe and widespread disease in immunodeficient adults. In addition, several animal poxviruses can be transmitted to humans as zoonosis. The most serious of these is monkeypox, which has an estimated human mortality of 1 to 10%. The poxviruses express a large number of host immune evasion genes that contribute to virulence. The purpose of this project is to increase our understanding of poxvirus host interactions, pathogenesis and the basis for immunity to poxviruses. Human genome-wide RNAi screens were conducted to determine host factors that impact poxvirus replication. During the past year we took advantage of the 235 available unique complete genome sequences of Orthopoxviruses (ORPV) and reannotated the approximately 200 genes of each to provide the first uniform gene nomenclature. We focused on the approximately 100 accessory genes, predicting the functions of uncharacterized genes, and reconstructed the history of their gain and loss during the evolution of ORPV. Most of the accessory genes were acquired in three major waves antedating the origin of ORPV from chordopoxviruses. The evolution of ORPV themselves was dominated by gene loss, with numerous genes lost at the base of each major group of ORPV. Examination of pairs of ORPV accessory genes that were either often or rarely lost concurrently during ORPV evolution allowed prediction of different types of functional interactions.