Defining the regulation of mitochondrial bioenergetics during virus infection

定义病毒感染期间线粒体生物能的调节

• 批准号: 10381483
• 负责人: Cora Nicole Betsinger
• 金额: $ 4.68万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381483
• 关键词: Address; Antiviral Agents; Antiviral Response; Bioenergetics; Biological Assay; Biology; Birth; Carbon; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Chronic Disease; Citric Acid Cycle; Congenital Abnormality; Cytomegalovirus; Defense Mechanisms; Development; Disease; Drug Design; Enzymes; Fellowship; Generations; Glycolysis; Goals; Health; Herpesviridae; Host Defense; Host Defense Mechanism; Human; Immune system; Immunocompromised Host; Impairment; Individual; Infection; Interdisciplinary Study; Knowledge; Lead; Link; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Microscopy; Mitochondria; Molecular Biology; Molecular Virology; Monitor; Organ failure; Oxidative Phosphorylation; Pathology; Pathway interactions; Population; Post-Translational Protein Processing; Prevalence; Production; Proteins; Proteomics; Pyruvate Dehydrogenase Complex; Regulation; Research; Respiratory Disease; Risk; Role; Side; Sirtuins; Structure; Testing; Therapeutic; Universities; Up-Regulation; Vaccines; Viral; Viral Proteins; Virus; Virus Assembly; Virus Diseases; Virus Replication; base; career development; cell growth regulation; deafness; enzyme activity; fatty acid biosynthesis; graduate student; human disease; human pathogen; interdisciplinary approach; interest; lipid biosynthesis; lipoamidase; metabolomics; mitochondrial metabolism; new therapeutic target; obligate intracellular parasite; pathogen; prevent; programs; student training; supportive environment; therapeutic target; therapy development; virology

PROJECT SUMMARY/ABSTRACT. Human cytomegalovirus (HCMV) is a ß-herpesvirus that infects over 50% of the world’s population and establishes lifelong infection in individuals. HCMV infection is a major concern in individuals with impaired or naïve immune systems, as it can lead to a range of diseases, including deafness, respiratory disease, and organ failure. Additionally, HCMV has garnered increased interest in recent years due to its implication in the emergence and progression of chronic diseases, such as cardiovascular disease and cancer. A striking feature of HCMV infection is the global rewiring of cellular metabolism for the increased production of biosynthetic precursors and energy for replication. The dysregulation of cellular metabolism during HCMV infection is necessary for its replication and has been linked to many of its pathologies, including its oncomodulatory capacity. However, we currently lack an understanding of the mechanisms underlying the metabolic alterations observed during infection. We recently discovered that the mitochondrial enzyme sirtuin 4 (SIRT4) is a potent antiviral factor during HCMV infection. Furthermore, we established SIRT4 as the first known mammalian cellular lipoamidase, removing the essential posttranslational modification lipoylation from the pyruvate dehydrogenase complex. This discovery points to SIRT4 as a critical regulator of cellular metabolism, but how SIRT4 exerts its antiviral function remains unknown. I hypothesize that SIRT4 functions in host defense during HCMV infection by opposing viral-induced changes in cellular metabolism. Further supporting the critical role of SIRT4 in antiviral response, I discovered that HCMV has acquired a mechanism to suppress its functions. My preliminary results demonstrate that SIRT4 is targeted for inhibition by the previously uncharacterized viral protein, pUL13. In my proposal, I will address both sides of this virus-host interplay. In Aim 1, a combination of molecular virology, microscopy, proteomics and metabolomics will be used to define SIRT4-mediated mechanisms of defense against HCMV infection. I will determine which specific SIRT4 enzymatic activities are required for antiviral response. In Aim 2, I will uncover how pUL13 inhibits SIRT4, as well as characterize its function in regulating cellular metabolism and mitochondrial bioenergetics. As a long-term objective, elucidating the functional interaction between SIRT4 and pUL13 can help explain how HCMV induces metabolic changes that promote disease. This knowledge can point to therapeutic targets for restoring metabolic health and for treating HCMV- linked pathologies. This research will take place in the Molecular Biology Department of Princeton University, a program known for its multidisciplinary research and supportive environment for graduate student training and career development.

项目总结/抽象。