Evolution and mechanism of restriction of herpesviruses by MxB

MxB限制疱疹病毒的进化和机制

基本信息

批准号：
10667144
负责人：
ADAM P. GEBALLE
金额：
$ 26.4万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-21 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667144
关键词：
Affect African African American population Alleles Biochemical Biological Assay Biotinylation Capsid Cebidae Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Codon Nucleotides Complement Coupled Cytomegalovirus Data Development Double Stranded DNA Virus Event Evolution Experimental Genetics Genes Genetic Determinism Genetic Polymorphism Genome Genomics Goals Health Herpesviridae Herpesvirus 1 Human Human Herpesvirus 2 Immune Immune system Immunologic Factors Infection Integration Host Factors Interferons Investigation Ligation Maps Mass Spectrum Analysis Measures Mediating Modeling Molecular Nuclear Import Orthologous Gene Pan Genus Phenotype Play Population Primates Protein Truncation Risk Role Sequence Analysis Shapes Side Simplexvirus Site Species Specificity Study models System Testing Time Variant Viral Viral Genome Viral Physiology Viral Proteins Virus Virus Diseases Work arm arms race candidate identification cofactor experimental study genetic signature genome editing insight nonhuman primate nonsynonymous mutation pathogen pathogenic virus pressure protein B protein Mx resistance gene resistant strain response viral transmission virus genetics

项目摘要

PROJECT SUMMARY/ABSTRACT Herpesviruses cause a substantial worldwide burden on human health. In response to infections by these and other pathogens, host cells express thousands of interferon-stimulated genes. One such gene encodes the myxovirus resistance protein B (MxB) that potently restricts several herpesviruses, including herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), and cytomegalovirus (CMV). MxB has been undergoing rapid evolution in primates, as reflected in genetic signatures of positive selection, suggesting that MxB has been engaged in arms races with viruses over millions of years. Intriguingly, unlike human MxB, the MxB alleles from several non-human primates do not inhibit HSV-1 replication. In contrast, all tested orthologs retain antiviral activity against CMV. These results suggest that human MxB, but not non-human primate orthologs, including the closely related chimpanzee gene, has evolved to restrict HSV-1. This scenario appears to be a rare example of the host side “winning” during an evolutionary arms race with a virus. To dissect the mechanism MxB utilizes to restrict HSV-1, studies in Aim 1 will define the role of specific residues that are necessary and sufficient to explain differing restrictive phenotypes of human and chimpanzee MxB orthologs. Experiments aiming to identify viral factors that are the targets of MxB, as well as which host co-factors are potentially required, will employ proximity ligation assays coupled with mass spectrometry. Building on the observation that HSV-2 strains vary in their sensitivity to human and chimpanzee MxB, Aim 2 will identify which other primate MxB orthologs restrict which strains of HSV-2, which will help elucidate the evolutionary trajectory of the development of the phenotype. Additionally, because human MxB restricts only a subset of HSV-2 strains, analyses of sequence differences among the strains will aid in the identification of viral determinants of MxB sensitivity. Together, this proposal will reveal the critical factors mediating the arms races between MxB and herpes simplex viruses and will aid in elucidating the anti-herpesvirus mechanism of MxB.

项目概要/摘要疱疹病毒对全球人类健康造成巨大负担。与其他病原体相比，宿主细胞表达数千个干扰素刺激基因，其中一个基因编码粘病毒抗性蛋白 B (MxB)，可有效限制多种疱疹病毒，包括单纯疱疹病毒病毒 1 (HSV-1)、单纯疱疹病毒 2 (HSV-2) 和巨细胞病毒 (CMV) 正在快速发展。灵长类动物的进化，正如正选择的遗传特征所反映的那样，表明 MxB 已被有趣的是，与人类 MxB 不同的是，MxB 等位基因来自数百万年。一些非人类灵长类动物不会抑制 HSV-1 复制，相反，所有测试的直向同源物都保留了抗病毒作用。这些结果表明人类 MxB 具有抗 CMV 活性，但非人类灵长类直系同源物，包括密切相关的黑猩猩基因已经进化到限制 HSV-1，这种情况似乎是一个罕见的例子。主机方在与病毒的进化军备竞赛中“获胜” 剖析 MxB 使用的机制。为了限制 HSV-1，目标 1 中的研究将定义特定残基的作用，这些残基对于限制 HSV-1 是必要且充分的。解释人类和黑猩猩 MxB 直系同源物的不同限制性表型。 MxB 的目标病毒因子以及潜在需要的宿主辅助因子将采用基于 HSV-2 毒株变化的观察，结合质谱分析进行邻近连接测定。由于对人类和黑猩猩 MxB 的敏感性，目标 2 将确定哪些其他灵长类 MxB 直系同源物限制哪些毒株是HSV-2的，这将有助于阐明其表型发展的进化轨迹。此外，由于人类 MxB 仅限制 HSV-2 毒株的一个子集，因此需要对序列差异进行分析该提案将有助于确定 MxB 敏感性的病毒决定因素。揭示介导 MxB 和单纯疱疹病毒之间军备竞赛的关键因素，并将有助于阐明 MxB 的抗疱疹病毒机制。