The tale of two receptors: Determining the role of lipoprotein receptors, SR-BI and LDL-R, in gammaherpesvirus infection

两种受体的故事：确定脂蛋白受体 SR-BI 和 LDL-R 在伽马疱疹病毒感染中的作用

• 批准号: 10320437
• 负责人: Carlie Anne Aurubin
• 金额: $ 4.88万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320437
• 关键词: 19 year old; Adult; Animal Model; Antiviral Response; Automobile Driving; B-Cell Lymphomas; B-Lymphocytes; Cardiovascular Diseases; Cells; Centers for Disease Control and Prevention (U.S.); Child; Cholesterol; Consumption; Coupled; DNA Sequence Alteration; Data; Development; Excretory function; Frequencies; Gene Expression; Health; High Density Lipoproteins; High Prevalence; Human; Immune response; In Vitro; Incidence; Individual; Infection; Label; Lead; Life; Lipids; Lipoprotein Receptor; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mammalian Cell; Modeling; Molecular; Murine herpesvirus 68; Mus; Nature; Oncogenic; Pathogenesis; Peripheral; Play; Population; Receptor Signaling; Risk Factors; Role; SR-BI receptor; Serum; Species Specificity; Spleen; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Tissues; Viral; Viral Genes; Virus; Virus Latency; Virus Replication; attenuation; experimental study; gammaherpesvirus; high density lipoprotein receptor; hypercholesterolemia; in vivo; insight; novel; novel therapeutics; pathogen; receptor; response; therapeutic target; tumorigenesis; virus related cancer; western diet

Proposal Summary Gammaherpesviruses are ubiquitous pathogens that establish life-long infections in most adults and are associated with several cancers, including B cell lymphomas. While the risk factors supporting viral tumorigenesis remain poorly understood, elevated viral latency and reactivation often precede oncogenesis. Recent studies have demonstrated that endogenous lipid synthesis supports gammaherpesvirus replication and latency. However, the role of exogenous cholesterol exchange during infection remains unknown. Therefore, this proposal aims to determine how exogenous cholesterol impacts viral latency and reactivation. Due to the high prevalence and species specificity of human gammaherpesviruses, the mouse pathogen murine herpesvirus 68 (MHV68) is widely utilized as the small animal model of gammaherpesvirus pathogenesis. A strength of this model is the ability to genetically modify the host to examine the cellular and molecular mechanism by which infection is controlled. Using this model, we have recently discovered an exciting role for lipoprotein receptors during gammaherpesvirus infection. Specifically, we have found that SR- BI, the high-density lipoprotein (HDL) receptor, supports MHV68 reactivation. While LDL-R, the low-density lipoprotein (LDL) receptor, suppresses MHV68 latency and reactivation. Therefore, we hypothesize that SR-BI exerts pro-viral effects, while LDL-R exerts anti-viral effects in infection. The in vitro and in vivio experiments proposed here will provide an extensive, yet focused analysis of the cellular and molecular importance of SR-BI and LDL-R expression in the spleen of the host during gammaherpesvirus infection. Importantly, successful completion of these studies will provide insight into the control of gammaherpesvirus infections, which would offer potential therapeutic targets for infected individuals particularly susceptible to the associated oncogenic effects of gammaherpesviruses.

提案摘要 γ疱疹病毒是普遍存在的病原体，其在大多数成年人中建立终身感染， 与几种癌症相关，包括B细胞淋巴瘤。虽然支持病毒的风险因素 肿瘤发生仍然知之甚少，病毒潜伏期和再激活的增加往往先于肿瘤发生。 最近的研究表明，内源性脂质合成支持γ疱疹病毒复制 和延迟。然而，外源性胆固醇交换在感染过程中的作用仍然未知。 因此，本提案旨在确定外源性胆固醇如何影响病毒潜伏期和再活化。 由于人γ疱疹病毒的高流行率和物种特异性，小鼠病原体 鼠疱疹病毒68（MHV 68）被广泛用作γ疱疹病毒的小动物模型 发病机制该模型的优点是能够遗传修饰宿主以检查细胞和细胞外基质。 控制感染的分子机制。利用这个模型，我们最近发现了一个 脂蛋白受体在γ疱疹病毒感染中的兴奋作用。具体来说，我们发现SR- BI，高密度脂蛋白（HDL）受体，支持MHV 68再活化。而LDL-R、低密度脂蛋白 脂蛋白（LDL）受体，抑制MHV 68潜伏期和再激活。因此，我们假设SR-BI 在感染中，LDL-R发挥前病毒作用，而LDL-R发挥抗病毒作用。 本文提出的体外和体内实验将提供一个广泛的，但集中的分析， SR-BI和LDL-R表达在宿主脾脏中的细胞和分子重要性 γ疱疹病毒感染重要的是，这些研究的成功完成将提供深入了解 控制γ疱疹病毒感染，这将为受感染者提供潜在的治疗靶点 特别易受γ疱疹病毒的相关致癌作用的影响。