Unravelling the mechanisms of virus host species jump

使病毒跨物种跳跃的机制，例如目前在非洲和美国爆发的冠状病毒SARS-CoV-2大流行和猴痘病毒的零星爆发，进入新的原始宿主物种，一直是科学兴趣的主题。就痘病毒而言，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。黏液瘤病毒（MYXV）是引起欧洲兔黏液瘤病（一种致死性疾病）的病原体。20世纪50年代初，在澳大利亚和欧洲引入MYXV以控制野生欧洲兔种群，这是在跨物种传播之后宿主-病毒共同进化的最佳现场记录实例。以MYXV为例，该病毒在其进化的宿主（Sylvilagus sp.）中是无致病性的，但在19世纪末跳入欧洲兔子体内后立即具有极高的致命性。直到最近，人们只知道MYXV在欧洲兔中引起粘液瘤病。然而，在2018年，在西班牙发现了死亡的野生伊比利亚野兔，其病变与粘液瘤病中观察到的病变一致，这表明最近可能在该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进行了调查，结果发现了一种新的重组MYXV，在此称为MYXV Toledo （MYXV- tol）。该新菌株的基因组与先前报道的在兔中传播的MYXV变体/菌株的基因组相同~ 99%，除了插入了一个长度约2,800 bp的新重组区域和三个中断的基因（M009L， M036L和M152R）。在这个新的重组插入区中，发现了一个新的痘病毒宿主范围基因的同源物M159，它与痘病毒c7l样宿主范围因子超家族同源。我们对重组病毒构建的初步结果证实，M159是允许兔MYXV-Tol物种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，我们提出以下目标来研究这种新的痘病毒宿主范围蛋白M159在MYXV-Tol中的作用机制以及它如何影响病毒的复制和毒力：目的1：阐明新鉴定的MYXV-Tol宿主范围蛋白M159的跨种跳跃的生物学机制。目的2：确定新的宿主范围蛋白M159与欧洲兔模型体内感染和复制的相关性。这一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中的作用。

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.