Unravelling the mechanisms of virus host species jump

使病毒跨物种跳跃的机制，例如目前的冠状病毒SARS-CoV-2大流行和非洲和美国的猴痘病毒零星爆发进入新的幼稚宿主物种，长期以来一直是科学兴趣的主题。在痘病毒的情况下，它被认为是由来自宿主和病毒的许多宿主范围因子调节的。粘液瘤病毒（Myxoma virus，MYXV）是粘液瘤病的病原体，粘液瘤病是欧洲家兔（Oryctolagus cuniculus）的致死性疾病。20世纪50年代初，在澳大利亚和欧洲引入MYXV来控制欧洲野兔种群，这是跨物种传播后宿主-病毒共同进化的最佳记录实例。在MYXV的情况下，该病毒在其进化宿主（Sylvilagus sp.）中是非致病性的。但在世纪后期，这种病毒在欧洲兔子身上传播后，立即就变得极其致命。直到最近，MYXV才被发现在欧洲兔子中引起粘液瘤病。然而，在2018年，在西班牙发现了死亡的野生伊比利亚野兔，其病变与在粘液瘤病中观察到的病变一致，这表明最近可能在伊比利亚野兔种群中爆发了粘液瘤病。我们对这些病变的病原体的调查导致鉴定出一种新的重组MYXV，在此称为MYXV Toledo（MYXV-Tol）。该新菌株的基因组与先前报告的在兔中传播的MYXV变体/菌株具有约99%的相同性，除了插入了一个新的重组区域（长度约为2，800 bp）和三个破坏的基因（M009 L、M036 L和M152 R）。在这个新的重组插入区，一个新的直向同源的痘病毒宿主范围基因称为M159，这是同源的痘病毒C7 L样宿主范围因子超家族。我们对重组病毒构建体的初步结果证实，M159是允许MYXV-Tol物种在野兔中跳跃的关键宿主范围蛋白。我们的目标是通过研究M159的功能来阐明这种跨物种溢出的机制。因此，我们建议解决以下目标，以研究这种新的痘病毒宿主范围蛋白M159在MYXV-Tol中的机制以及它如何影响病毒复制和毒力：目的1：阐明新鉴定的MYXV-Tol宿主范围蛋白M159的跨物种跳跃的生物学机制。目的2：确定新的宿主范围蛋白M159在欧洲兔模型中体内感染和复制的相关性。这项R21提案将使我们能够深入了解MYXV-Tol宿主范围蛋白M159在病毒复制，宿主免疫系统调节和致病性方面的作用。

The mechanisms enabling cross-species jumps of viruses, for example current coronavirus SARS-CoV-2 pandemic and sporadic outbreak of monkeypox virus in Africa and USA into a new naive host species have long been a subject of scientific interest. In the case of poxviruses, it is thought to be modulated by many host range factors derived from both the host and virus. Myxoma virus (MYXV) is the causative agent of myxomatosis, a lethal disease in the European rabbit (Oryctolagus cuniculus). The introduction of MYXV to control feral European rabbit populations in Australia and Europe, in the early 1950s, presents the best-documented field example of host–virus co-evolution, following a cross-species transmission. In the case of MYXV, the virus is nonpathogenic in its evolutionary host (Sylvilagus sp.) but was extremely lethal immediately after it leaped into European rabbits in the late 19th century. Until recently, MYXV was only known to cause myxomatosis in European rabbits. However, in 2018, deceased wild Iberian hares with lesions consistent with those observed in myxomatosis were found in Spain, suggesting a likely recent outbreak of myxomatosis in this Iberian hare population. Our inquiry into the causative agent of these lesions resulted in the identification of a new recombinant MYXV, hereby referred to as MYXV Toledo (MYXV-Tol). The genome of this new strain is ~99 % identical to MYXV variants /strains previously reported circulating in rabbits, with the exception of the insertion of a new recombinant region ~2,800 bp in length and three disrupted genes (M009L, M036L and M152R). In this novel recombinant insertion region, a new orthologue of a poxvirus host range gene called M159 was identified, which is homologous to the poxvirus C7L-like host range factor superfamily. Our preliminary results with recombinant virus constructs confirm that M159 is the key host range protein that allowed MYXV-Tol species leap in hares. Our goal is to elucidate the mechanisms of this cross-species spillover by studying M159 functions. We thereby propose to address the following aims to investigate the mechanisms of this novel poxvirus host range protein M159 in MYXV-Tol and how it influences virus replication and virulence: Aim 1: Elucidate the biological mechanism(s) of cross-species jumping of the newly identified MYXV-Tol host range protein M159. Aim 2: Define the relevance of the new host range protein, M159, for in vivo infection and replication in a European rabbit model. This R21 proposal will enable us to gain insight into the role MYXV-Tol host range protein M159 plays on the virus replication, regulation of host immune system, and pathogenicity.