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