Identification of the gene controlling murine retrovirus in YBR mice

YBR小鼠体内控制鼠逆转录病毒的基因的鉴定

• 批准号: 10724724
• 负责人: Tatyana V Golovkina
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724724
• 关键词: Alleles; Antibodies; Automobile Driving; Candidate Disease Gene; Chromosome 18; Computer Analysis; Cytotoxic T-Lymphocytes; Disease; Dominant Genes; Exhibits; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Goals; HIV; Health; Human; Immune response; Inbred Mouse; Individual; Infection; Inherited; Knowledge; Lymphocyte; Lymphoid Cell; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Maps; Mediating; Milk; Modeling; Mouse Mammary Tumor Virus; Mouse Strains; Mucous Membrane; Mus; Names; Natural Killer Cells; Population; Predisposition; Resistance; Retroviridae; Study models; Susceptibility Gene; T-Lymphocyte and Natural Killer Cell; Therapeutic; Tumor Virus Infections; Vaccines; Variant; Viral; Virus; Virus Diseases; Virus Replication; YBR Mouse; attenuation; candidate identification; cytotoxic CD8 T cells; experimental study; genetic makeup; human pathogen; microbial; neutralizing antibody; pathogen; pathogenic virus; pup; resistance gene; resistance mechanism; response; suckling; transmission process; tumor; tumorigenesis

Abstract Differential responses to viral infections are influenced by the genetic makeup of the host. As a result, sensitivity of humans to viral infections varies considerably, with some individuals withstanding strong viral pathogens, such as the retrovirus, human immunodeficiency virus (HIV). Studies of inherited resistance to retroviruses in human populations are enormously complicated, making it difficult to dissect strong antiviral effector mechanisms that can be taken advantage of when developing therapeutics and vaccines. However, the variations in the susceptibility of inbred mice to viral infections make the mouse an excellent model for mapping mechanisms and genes driving mammalian susceptibility and resistance to retroviruses. Exogenous mouse mammary tumor virus (MMTV) represents a well-studied model of mucosally transmitted retrovirus. The virus is acquired through the milk in the gut of suckling pups and is passed to the mammary glands by lymphocytes, where it induces mammary gland tumors after several cycles of re-infection/re-integration. Susceptibility to exogenous MMTV infection and subsequent mammary tumorigenesis differs drastically among different mouse strains, ranging from absolute resistance to high susceptibility. Mice from the MMTV-resistant YBR/Ei (YBR) strain become virus-infected, but do not develop mammary tumors, produce reduced virus titers, and efficiently eliminate the pathogen in successive generations. In our preliminary studies we found that the unique mechanism of virus control in YBR mice is unrelated to anti-virus antibodies (Abs), virus-specific CD8+ cytotoxic T lymphocytes, natural killer (NK) cells, and NK T cells, but depends on Thy1+ lymphoid cells. Moreover, the virus restriction is controlled by a single, dominant locus, which we named attenuation of virus titers (avt) and have mapped to chromosome 18. Using genetic studies and computational analyses, we will identify the gene responsible for this remarkable effector mechanism.

抽象的 对病毒感染的差异反应受宿主的遗传组成的影响。因此， 人类对病毒感染的敏感性差异很大，有些人承受强病毒 病原体，例如逆转录病毒，人类免疫缺陷病毒（HIV）。对遗传性的研究 人群中的逆转录病毒非常复杂，因此难以剖析强抗病毒 开发治疗剂和疫苗时可以利用的效应机制。然而， 近交小鼠对病毒感染的敏感性的变化使小鼠成为极好的模型 映射机制和基因驱动哺乳动物的敏感性和对逆转录病毒的抗性。外源 小鼠乳腺肿瘤病毒（MMTV）代表了粘膜传播逆转录病毒的良好模型。这 病毒是通过哺乳幼犬的牛奶获得的，并通过 淋巴细胞，在几次重新感染/重新整合周期后，它诱导乳腺肿瘤。 外源MMTV感染和随后的乳腺肿瘤发生的敏感性在 不同的小鼠菌株，从绝对抗性到高敏感性。抗MMTV的老鼠 YBR/EI（YBR）菌株感染了病毒，但不会产生乳腺肿瘤，会产生降低的病毒滴度， 并有效地消除了连续几代人的病原体。在我们的初步研究中，我们发现 YBR小鼠病毒控制的独特机制与抗病毒抗体（ABS），病毒特异性CD8+无关 细胞毒性T淋巴细胞，天然杀伤（NK）细胞和NK T细胞，但取决于Thy1+淋巴样细胞。 此外，病毒限制受单个主要基因座的控制，我们将其命名为病毒的衰减 滴度（AVT）并已映射到18号染色体。使用遗传研究和计算分析，我们将 确定负责这种非凡效应器机制的基因。