Antiviral responses of host mediated S-nitrosylation of viral proteins.

宿主介导的病毒蛋白 S-亚硝基化的抗病毒反应。

• 批准号: 10376727
• 负责人: Eain A Murphy
• 金额: $ 40.5万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-23 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376727
• 关键词: Antiviral Response; Biological; Biological Process; Biotin; Cells; Cysteine; Cytokine Gene; Cytomegalovirus; Cytomegalovirus Infections; DNA; DNA Viruses; Data; Disease; Equilibrium; Foundations; Genetic Transcription; Goals; Growth; Hematopoietic stem cells; Herpesviridae; Host Defense; Human; IRF3 gene; Immune response; Immune system; Immunocompetent; Individual; Infection; Innate Immune Response; Integration Host Factors; Interferon Type I; Intervention; Laboratories; Lytic; Lytic Phase; Mediating; Methodology; Modification; Morbidity - disease rate; Mutate; Mutation; Nitric Oxide; Outcome; Pathogenesis; Pathway interactions; Play; Population; Post-Translational Protein Processing; Production; Protein S; Proteins; Proteomics; Regulation; Repression; Research; Role; SKIL gene; Serine; Stimulator of Interferon Genes; Sulfhydryl Compounds; Symptoms; Testing; Therapeutic Intervention; Transcriptional Activation; Vaccines; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; arm; cytokine; design; insight; knowledge base; latent infection; lytic replication; macrophage; mortality; new therapeutic target; novel; pathogen; protein function; response; virology

Human cytomegalovirus (HCMV) is a common pathogen that has infected a majority of the human population. While symptoms of HCMV are generally resolved in immunocompetent individuals, the virus remains for the lifetime within the host as a latent infection is established in the hematopoietic stem cells. HCMV has co- evolved with humans and as such, the virus as adapted to undermine host cell antiviral responses. How HCMV undermines these responses is not fully known. Our research has found that an understudied protein modification, S-nitrosylation, plays a role in how HCMV interacts with the antiviral response. We found that viral proteins critical for efficient lytic replication are post translationally modified with nitric oxide groups and that the resulting modifications alter the viral proteins ability to limit antiviral responses. We propose to mechanistically investigate how these modifications impact HCMV protein functions and to identify the impact of S-nitrosylation on HCMV replication. Completion of the aims above will contribute significantly to our knowledge the regulation of biological functions of critical viral factors as well as identify the mechanism by which viruses weaken host defenses against infection. This work will lay the foundation in identifying novel therapeutic targets for a pathogen that lacks a vaccine or a cure.

人巨细胞病毒（HCMV）是一种常见的病原体，已感染了大多数人口。虽然HCMV的症状通常在免疫功能正常的个体中消退，但病毒在宿主体内终生存在，因为在造血干细胞中建立了潜伏感染。HCMV与人类共同进化，因此，病毒适应破坏宿主细胞的抗病毒反应。HCMV如何破坏这些反应尚不完全清楚。我们的研究发现，一个未充分研究的蛋白质修饰，S-亚硝基化，在HCMV如何与抗病毒反应相互作用中发挥作用。我们发现，病毒蛋白质的关键有效裂解复制后修饰一氧化氮基团和由此产生的修改改变病毒蛋白质的能力，限制抗病毒反应。我们建议从机制上研究这些修饰如何影响HCMV蛋白的功能，并确定S-亚硝基化对HCMV复制的影响。上述目标的实现将有助于我们了解病毒关键因子的生物学功能，并确定病毒削弱宿主抗感染防御能力的机制。这项工作将为确定缺乏疫苗或治愈方法的病原体的新治疗靶点奠定基础。