Evolution and mechanism of restriction of herpesviruses by MxB

MxB限制疱疹病毒的进化和机制

• 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
• 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

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.

项目摘要/摘要 疱疹病毒在全球范围内对人类健康造成了巨大的燃烧。响应这些感染和 其他病原体，宿主细胞表达成千上万的干扰素刺激的基因。这样的基因编码 粘液病毒抗性蛋白B（MXB）可能限制了几种疱疹病毒，包括单纯疱疹 病毒1（HSV-1），单纯疱疹病毒2（HSV-2）和巨细胞病毒（CMV）。 MXB一直在迅速 私人的进化，正如阳性选择的遗传特征所反映的那样，表明MXB已经是 在数百万年内与病毒一起参加了军备竞赛。有趣的是，与人类MXB不同，MXB等位基因 几个非人类隐私不会抑制HSV-1复制。相反，所有测试的直系同源物保留抗病毒 针对CMV的活动。这些结果表明人类MXB，但没有非人类灵长类动物直系同源物 密切相关的黑猩猩基因已演变为限制HSV-1。这种情况似乎是一个罕见的例子 在带有病毒的进化武器竞赛中，主人方面“获胜”。剖析机制MXB使用 为了限制HSV-1，AIM 1中的研究将定义特定残差的作用，而这些残留物是必要且足够的 解释人和黑猩猩MXB直系同源物的限制性表型。实验旨在识别 将是MXB靶标的病毒因素以及可能需要哪种宿主共同因素 接近连接测定与质谱法结合。基于HSV-2菌株变化的观察 在对人类和黑猩猩MXB的敏感性中，AIM 2将确定其他灵长类动物MXB直系同源物限制 哪些HSV-2菌株将有助于阐明表型发展的进化轨迹。 另外，由于人类MXB仅限制了HSV-2菌株的子集，所以序列差异的分析 在菌株中，将有助于鉴定MXB敏感性的病毒决定剂。在一起，这个建议将 揭示介导MXB和单纯疱疹病毒之间的武器种族的关键因素，并将有助于 阐明MXB的抗hepesvirus机制。