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 对病毒感染的不同反应受到宿主基因组成的影响。因此， 人类对病毒感染的敏感性差异很大，有些人能耐受较强的病毒感染 病原体，例如逆转录病毒、人类免疫缺陷病毒（HIV）。遗传性耐药性研究 人群中的逆转录病毒非常复杂，因此很难剖析强效抗病毒药物 开发治疗方法和疫苗时可以利用的效应机制。然而， 近交系小鼠对病毒感染的易感性存在差异，这使得该小鼠成为了极好的模型。 绘制哺乳动物对逆转录病毒的易感性和抗性的机制和基因。外源性 小鼠乳腺肿瘤病毒（MMTV）代表了一种经过充分研究的粘膜传播逆转录病毒模型。这 病毒是通过哺乳幼崽肠道中的乳汁获得的，并通过乳腺传播到乳腺。 淋巴细胞，在几个循环的再感染/再整合后诱发乳腺肿瘤。 不同人群对外源性 MMTV 感染和随后的乳腺肿瘤发生的易感性存在显着差异 不同的小鼠品系，从绝对抗性到高度易感性。 MMTV 抗小鼠 YBR/Ei (YBR) 株被病毒感染，但不会产生乳腺肿瘤，病毒滴度降低， 并有效消除连续几代的病原体。在我们的初步研究中我们发现 YBR 小鼠独特的病毒控制机制与抗病毒抗体 (Abs)、病毒特异性 CD8+ 无关 细胞毒性 T 淋巴细胞、自然杀伤 (NK) 细胞和 NK T 细胞，但依赖于 Thy1+ 淋巴细胞。 此外，病毒限制是由单个显性位点控制的，我们将其称为病毒减毒 滴度 (avt) 并已映射到 18 号染色体。利用遗传研究和计算分析，我们将 确定负责这种显着效应机制的基因。