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Unravelling the mechanisms of virus host species jump

揭示病毒宿主物种跳跃的机制

基本信息

批准号：
10289093
负责人：
Grant McFadden
金额：
$ 23.55万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-26 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289093
关键词：
Address Africa Animals Antiviral Agents Australia Automobile Driving Biological Biological Models Blood COVID-19 outbreak COVID-19 pandemic Cancer cell line Cell Death Cell Line Cells Complex Coronavirus DNA cassette Disease Disease Outbreaks Disease Progression Europe European Evolution Family Family member Gene Order Genes Genome Genomic Segment Goals Government Hares Health Histology Human Human Cell Line Immune system In Vitro Infection Knock-out Length Lesion Leukocytes Mediating Modeling Monkeypox virus Myxoma virus New Zealand Organ Oryctolagus cuniculus Outcome Pathogenesis Pathogenicity Pathway interactions Peripheral Blood Mononuclear Cell Play Polynucleotide Adenylyltransferase Population Poxviridae Protein Family Proteins Proteomics Province Recombinants Regulation Reporting Role Sampling Source Spain Systemic infection Tanapox viruses Testing Thymidine Kinase Tissues Ungulate Variant Viral Viral Proteins Virion Virulence Virus Virus Replication Wild Animals Zoonoses authority base cancer cell cross-species transmission in vivo in vivo evaluation insight interest member novel protein function recombinant virus

项目摘要

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.

病毒跨物种跳跃的机制，例如当前的冠状病毒 SARS-CoV-2 大流行以及非洲和美国零星爆发的猴痘病毒进入新的幼稚宿主物种，长期以来一直是科学界关注的主题。就痘病毒而言，它被认为受到来自宿主和病毒的许多宿主范围因素的调节。粘液瘤病毒（MYXV）是粘液瘤病的病原体，粘液瘤病是欧洲兔（Oryctolagus cuniculus）的一种致命疾病。 20 世纪 50 年代初，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与病毒共同进化的最有记录的现场例子。就 MYXV 而言，该病毒在其进化宿主（西尔维拉格斯属）中是非致病性的，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，人们才知道 MYXV 会引起欧洲兔子的粘液瘤病。然而，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，这表明该伊比利亚野兔种群最近可能爆发了粘液瘤病。我们对这些病变的病原体的研究导致了一种新的重组 MYXV 的鉴定，特此称为 MYXV Toledo (MYXV-Tol)。这种新毒株的基因组与先前报道的在兔子中传播的 MYXV 变种/毒株的基因组相同，但插入了长度约为 2,800 bp 的新重组区域和三个破坏的基因（M009L、M036L 和 M152R）。在这个新的重组插入区域中，鉴定出一种名为 M159 的痘病毒宿主范围基因的新直系同源物，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 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 MYXV-Tol 中这种新型痘病毒宿主范围蛋白 M159 的机制及其如何影响病毒复制和毒力：目标 1：阐明新鉴定的 MYXV-Tol 宿主范围蛋白 M159 跨物种跳跃的生物学机制。目标 2：确定新宿主范围蛋白 M159 与欧洲兔模型体内感染和复制的相关性。该 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。