The Role of Trim Proteins in Regulating Norovirus Replication and Tropism

修剪蛋白在调节诺如病毒复制和趋向性中的作用

• 批准号: 10658519
• 负责人: Robert C. Orchard
• 金额: $ 47.91万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-08 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658519
• 关键词: Animal Model; Biological Models; Biology; Calicivirus; Cell Shape; Cells; Cellular Tropism; Data; Diarrhea; Escape Mutant; Evolution; Family; Gastroenteritis; Genetic Variation; Goals; Human; In Vitro; Infection; Integration Host Factors; Intestines; Journals; Knowledge; Life Cycle Stages; Molecular; Mus; Nonstructural Protein; Norovirus; Outcome; Pathogenesis; Peptide Hydrolases; Physiological; Proteins; RNA Viruses; Resistance; Role; Route; Shapes; System; TRIM Family; TRIM Gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tropism; Ubiquitination; Viral; Viral Pathogenesis; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; diarrheal disease; enteric infection; fitness; genetic evolution; in vivo; insight; link protein; member; mouse model; new therapeutic target; overexpression; pathogen; permissiveness; pressure; protein function; receptor; ubiquitin-protein ligase; vaccine access; viral fitness; virology; virus tropism

Viral tropism, or the range of cells, tissues, or species that a virus can infect, is an important concept to understand viral pathogenesis and the emergence of new viral diseases. Noroviruses are the leading cause of diarrheal diseases worldwide, yet little is known about what contributes to norovirus tropism. Filling in this knowledge gap is crucial to better comprehend norovirus biology, pathogenesis, and therapeutic options. Human noroviruses do not robustly replicate in small animal models and thus murine norovirus (MNV) has emerged as a model system to discover mechanisms of norovirus biology and tropism. Over the past several years, it has been established that MNV strains can infect different cells and tissues in mice despite similar routes of inoculation. The molecular basis for these tropism differences are largely unknown. We recently demonstrated that CD300lf is a universal MNV receptor. This finding demonstrates that the primary mechanism for diversifying MNV strain tropism is not differential receptor utilization. These findings suggest the possibility that unknown host antiviral proteins function as restriction factors that limit the tissue and cellular replication of certain MNV strains. Yet, restriction factors for any norovirus have defied molecular identification. Here, we build upon our initial identification of Trim7 and Trim47 as MNV restriction factors. TRIM proteins are ubiquitin E3 ligases, although the substrates and antiviral mechanisms of Trim7 and Trim47 are currently unknown. While Trim7 broadly inhibits MNV strains from replicating, Trim47 selectively inhibits certain MNV strains. In other viral systems, TRIM proteins are responsible for shaping the cellular and species tropism of viruses. Therefore, we hypothesize that Trim7 and Trim47 constitute a family of TRIM restriction factors that regulate the tropism of noroviruses, including human norovirus. In Specific Aim 1, we will determine the molecular mechanism of Trim7 and Trim47 inhibition of MNV. We will also determine the breadth of the antiviral activity of Trim7 and Trim47 on related viruses, including human norovirus. In Specific Aim 2, we will define the physiological role of Trim7 and Trim47 in shaping the cells and tissues that are permissive for MNV replication in vivo. We will also determine the in vivo fitness tradeoffs for viruses that acquire resistance to Trim7 and Trim47 .This project leverages the MNV model system to uncover new mechanisms of viral restriction by a pair of poorly understood TRIM proteins. It will provide insight into drivers of norovirus tropism and evolution.

病毒疗法或病毒可能感染的细胞，组织或物种的范围是了解病毒发病机理和新病毒疾病的出现的重要概念。诺如病毒是全球腹泻疾病的主要原因，但对有助于诺如病毒的性质主义的原因知之甚少。填补这一知识差距对于更好地理解诺如病毒生物学，发病机理和治疗选择至关重要。人类诺如病毒在小动物模型中不强大地复制，因此诺如病毒（MNV）已成为一种模型系统，以发现诺如病毒生物学和tropismism的机制。在过去的几年中，尽管接种相似，但已经确定MNV菌株可以在小鼠中感染不同的细胞和组织。这些朝向主义差异的分子基础在很大程度上未知。我们最近证明CD300LF是一种通用MNV受体。这一发现表明，多元化MNV菌株tropism的主要机制不是差异受体利用。这些发现表明，未知的宿主抗病毒蛋白作为限制某些MNV菌株的组织和细胞复制的限制因素的可能性。然而，任何诺如病毒的限制因素都违反了分子鉴定。在这里，我们基于对TRIM7和TRIM47作为MNV限制因素的初始识别。 Trim蛋白是泛素E3连接酶，尽管TRIM7和TRIM47的底物和抗病毒机制目前尚不清楚。虽然TRIM7广泛抑制MNV菌株复制，但TRIM47有选择地抑制某些MNV菌株。在其他病毒系统中，修剪蛋白负责塑造病毒的细胞和物种向性。因此，我们假设TRIM7和TRIM47构成了调节包括人类诺如病毒在内的诺诺未病毒的北极病的限制因素的家族。在特定的目标1中，我们将确定MNV的TRIM7和TRIM47抑制的分子机制。我们还将确定TRIM7和TRIM47对包括人诺如病毒在内的相关病毒的抗病毒活性的广度。在特定目标2中，我们将定义TRIM7和TRIM47在体内允许MNV复制的细胞和组织中的生理作用。我们还将确定获得对TRIM7和TRIM47耐药性的病毒的体内适应性权衡。该项目利用MNV模型系统通过一对知识的Trim蛋白来揭示病毒限制的新机制。它将提供对诺如病毒往返和进化的驱动因素的见解。