Endogenous Retroviruses and the Immune Response to Pathogens

内源性逆转录病毒和对病原体的免疫反应

• 批准号: 8492239
• 负责人: Jaquelin Page Dudley
• 金额: $ 22.61万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492239
• 关键词: Address; Affect; Anti-Retroviral Agents; Antigen-Presenting Cells; Autoimmune Diseases; Bacteria; Betaretrovirus; Binding; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Chromosomes; Chromosomes, Human, Pair 8; Chronic; Communicable Diseases; Complex; Congenic Mice; Cultured Cells; DNA; Data; Development; Disease; Endogenous Retroviruses; Friend Murine Leukemia Virus; Genes; Goals; Gram-Negative Bacteria; HERVs; HIV; Human; Human Genome; Immune response; Immune system; Immunity; Immunodeficiency and Cancer; Inbred BALB C Mice; Individual; Infection; Interleukin-4; Knockout Mice; Laboratories; Lymphocyte; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Milk; Modeling; Mouse Mammary Tumor Virus; Mouse Strains; Mus; Natural Immunity; Pathogenesis; Pharmaceutical Preparations; Phenotype; Predisposition; Production; Protein Binding; Proteins; Proviruses; RNA; Repression; Resistance; Retroviral Vector; Retroviridae; Role; Seminal; Shapes; Superantigens; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Transgenic Animals; Transgenic Mice; Translating; Vaccines; Vibrio cholerae; Viral; Virus; Virus Diseases; Virus Replication; ZNF145 gene; adaptive immunity; c-myc Genes; congenic; cytokine; env Gene Products; genetic manipulation; genetic regulatory protein; infectious disease treatment; killer T cell; mRNA Export; mRNA Expression; mammalian genome; mutant; novel; novel strategies; pathogen; protein expression; public health relevance; reconstitution; research study; resistance mechanism; response; thymocyte; tissue culture; transcription factor; transmission process

DESCRIPTION (provided by applicant): Approximately 8% of the human genome is composed of integrated copies of retroviral DNA. At least some of the endogenous retroviruses are transcribed and translated into proteins, but the functional consequences are unclear. Nevertheless, endogenous retroviruses encode many of the same genes as exogenous retroviruses, which are known to manipulate the immune system to allow chronic infections and disease. For example, endogenous proviruses related to the betaretrovirus mouse mammary tumor virus (MMTV) (aka Mtvs) are known to affect the T-cell repertoire of mice through expression of superantigen (Sag). A novel mouse strain, BALB/Mtv-null, has been developed that is congenic to BALB/c mice, but lacks endogenous Mtv proviruses. We have shown that the Mtv-null mice are more resistant to specific viral and bacterial pathogens, including exogenous MMTV, Friend murine leukemia virus, and the gram- negative bacterium, Vibrio cholerae, compared to the parental BALB/c strain. Although the mechanism of resistance may not be the same for each pathogen, preliminary data indicate that Mtv-null mice have increased numbers of mature invariant natural killer T (iNKT) cells compared to those of BALB/c mice. Interestingly, individual Mtv proviruses, which are located on different mouse chromosomes and have different numbers of genes, do not contribute equally to iNKT phenotype or resistance to pathogen infection. Susceptibility to V. cholerae is reconstituted by any one of three endogenous Mtvs, including one that encodes only Sag. Nevertheless, the Sag-only Mtv provirus only partially reconstitutes susceptibility to MMTV-induced mammary tumors, and does not increase susceptibility to Friend virus disease. On the other hand, a complete provirus, Mtv9, reconstitutes susceptibility to both MMTV and Friend virus. Complete MMTV proviruses encode Rem, a Rev-like protein related to the human endogenous virus type K (HERV-K) Rec protein. Rec has been shown to interact with the transcription factor, PLZF, which controls the function and maturation of iNKT cells. We propose that Rev-like proteins encoded by specific murine and human retroviruses control the immune response to pathogens through PLZF and iNKT cells. In the first specific aim, transgenic mice expressing either rem or rec will be developed and characterized for their effects on the maturation of iNKT cells and susceptibility to exogenous retroviruses. In the second specific aim, primary thymocytes will be transduced with retroviruses expressing either rem or rec to determine their effects on cellular phenotype and PLZF function. These experiments will increase our understanding of T- cell selection and differentiation as well as the immune response to pathogens. The long-term goal of this proposal is the development of new approaches for treatment of infectious disease.

描述（由申请人提供）：约8%的人类基因组由整合的逆转录病毒DNA拷贝组成。至少有一些内源性逆转录病毒被转录并翻译成蛋白质，但功能后果尚不清楚。然而，内源性逆转录病毒编码许多与外源性逆转录病毒相同的基因，已知外源性逆转录病毒操纵免疫系统以允许慢性感染和疾病。例如，已知与β逆转录病毒小鼠乳腺肿瘤病毒（MMTV）（又名Mtvs）相关的内源性前病毒通过表达超抗原（Sag）影响小鼠的T细胞库。一种新的小鼠品系，BALB/Mtv-null，已开发的是同源的BALB/c小鼠，但缺乏内源性Mtv前病毒。我们已经表明，与亲本BALB/c菌株相比，Mtv缺失小鼠对特定的病毒和细菌病原体更具抗性，包括外源性MMTV、Friend鼠白血病病毒和革兰氏阴性细菌霍乱弧菌。虽然每种病原体的耐药机制可能不一样，但初步数据表明，与BALB/c小鼠相比，Mtv-null小鼠的成熟不变自然杀伤T（iNKT）细胞数量增加。有趣的是，位于不同小鼠染色体上并具有不同数量基因的单个Mtv前病毒对iNKT表型或对病原体感染的抗性的贡献并不相等。对霍乱弧菌的易感性由三种内源性Mtv中的任何一种重建，包括仅编码Sag的Mtv。然而，Sag唯一的Mtv前病毒仅部分地重建了对MMTV诱导的乳腺肿瘤的易感性，并且不增加对Friend病毒病的易感性。另一方面，完整的前病毒Mtv 9可以重建对MMTV和Friend病毒的易感性。完整的MMTV前病毒编码Rem，Rem是一种与人内源性K型病毒（HERV-K）Rec蛋白相关的Rev样蛋白。已显示Rec与转录因子PLZF相互作用，PLZF控制iNKT细胞的功能和成熟。我们提出，由特定的鼠和人逆转录病毒编码的Rev样蛋白通过PLZF和iNKT细胞控制对病原体的免疫应答。在第一个具体目标中，将开发表达rem或rec的转基因小鼠，并表征其对iNKT细胞成熟和对外源性逆转录病毒易感性的影响。在第二个具体目标中，将用表达rem或rec的逆转录病毒转导原代胸腺细胞，以确定它们对细胞表型和PLZF功能的影响。这些实验将增加我们对T细胞选择和分化以及对病原体的免疫反应的理解。该提案的长期目标是开发治疗传染病的新方法。