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.

摘要 对病毒感染的不同反应受宿主基因组成的影响。因此，在本发明中， 人类对病毒感染的敏感性差异很大，有些人能抵抗强病毒感染， 病原体，如逆转录病毒、人类免疫缺陷病毒（HIV）。遗传抗性的研究 人类中的逆转录病毒非常复杂，因此很难分离出强大的抗病毒药物。 在开发治疗剂和疫苗时可以利用的效应器机制。然而，在这方面， 近交系小鼠对病毒感染的易感性的变化使得小鼠成为用于 绘制哺乳动物对逆转录病毒易感性和抗性的机制和基因。外源 小鼠乳腺肿瘤病毒（MMTV）代表了一种被充分研究的粘膜传播逆转录病毒模型。的 病毒通过乳鼠肠道中的乳汁获得，并通过 淋巴细胞，在几个周期的再感染/再整合后诱导乳腺肿瘤。 对外源性MMTV感染和随后的乳腺肿瘤发生的易感性在以下人群中差异很大： 不同的小鼠品系，从绝对抗性到高敏感性。MMTV耐药小鼠 YBR/Ei（YBR）菌株被病毒感染，但不发生乳腺肿瘤，产生降低的病毒滴度， 并在连续世代中有效地消除病原体。在我们的初步研究中，我们发现 YBR小鼠中病毒控制的独特机制与抗病毒抗体（Abs）、病毒特异性CD 8 + 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Thy 1+淋巴细胞。 此外，病毒的限制作用是由一个单一的、显性的位点控制的，我们称之为病毒减毒 滴度（AVT），并已定位于染色体18。利用遗传学研究和计算分析，我们将 确定负责这种显著效应机制的基因。