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: 8652435
• 负责人: Jaquelin Page Dudley
• 金额: $ 18.77万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652435
• 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）：大约 8% 的人类基因组由逆转录病毒 DNA 的整合拷贝组成。至少一些内源性逆转录病毒被转录并翻译成蛋白质，但其功能后果尚不清楚。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可以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）相关的内源性原病毒通过超抗原（Sag）的表达影响小鼠的T细胞库。一种新的小鼠品系 BALB/Mtv-null 已被开发出来，它与 BALB/c 小鼠是同源的，但缺乏内源性 Mtv 原病毒。我们已经证明，与亲本 BALB/c 菌株相比，Mtv 缺失小鼠对特定病毒和细菌病原体具有更强的抵抗力，包括外源 MMTV、Friend 鼠白血病病毒和革兰氏阴性细菌霍乱弧菌。尽管每种病原体的耐药机制可能不同，但初步数据表明，与 BALB/c 小鼠相比，Mtv 缺失小鼠的成熟不变自然杀伤 T (iNKT) 细胞数量有所增加。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 原病毒对 iNKT 表型或对病原体感染的抵抗力的贡献并不相同。对霍乱弧菌的易感性是由三种内源性 Mtv 中的任何一种重建的，包括一种仅编码 Sag 的 Mtv。然而，Sag-only Mtv 原病毒仅部分重建对 MMTV 诱导的乳腺肿瘤的易感性，并且不会增加对 Friend 病毒病的易感性。另一方面，完整的原病毒 Mtv9 重建了对 MMTV 和 Friend 病毒的易感性。完整的 MMTV 原病毒编码 Rem，这是一种与人内源性病毒 K 型 (HERV-K) Rec 蛋白相关的 Rev 样蛋白。 Rec 已被证明与转录因子 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反应。在第一个具体目标中，将开发表达 rem 或 rec 的转基因小鼠，并对其对 iNKT 细胞成熟和对外源逆转录病毒易感性的影响进行表征。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。这些实验将增进我们对 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。