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Mechanism of Resistance to MMTV Induced Mammary Tumors

MMTV诱发乳腺肿瘤的耐药机制

基本信息

批准号：
7617384
负责人：
Tatyana V Golovkina
金额：
$ 2万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7617384
关键词：
Acquired Immunodeficiency Syndrome Alleles Anti-Retroviral Agents Antibodies Antibody Formation C3H/HeN Mouse CD4 Positive T Lymphocytes Candidate Disease Gene Cells Chromosomes, Human, Pair 15 Chromosomes, Human, Pair 17 Congenic Mice Cytokine Inducible SH2-Containing Protein Development Disease Genes Genetic Human Human Virus Immune response Immune system Immunity Immunoglobulin Class Switching In Vitro Inbred Mouse Infection Infection prevention Inherited Interferons Interleukin-12 Investigation Knowledge Lead Life Location Mammary Neoplasms Maps Mediating Modeling Molecular Monitor Mouse Mammary Tumor Virus Mouse Strains Murine leukemia virus Mus Mutate Names Numbers Play Population Predisposition Production Recessive Genes Resistance Retroviridae Role Signal Transduction Staining method Stains Susceptibility/Resistance Gene T-Cell Leukemia Transcriptional Activation Transgenic Mice Tumor Virus Infections Up-Regulation Vaccines Variant Viral Viral Antigens Virion Virus Virus Diseases Virus Replication base in vivo inhibitor/antagonist macrophage mammary tumor virus neutralizing antibody pathogen resistance mechanism response toll-like receptor 4

项目摘要

Retroviruses cause lethal diseases in humans by defeating host immune responses. While studies of inherited resistance to retroviruses in human populations are enormously difficult, the variations in the susceptibility of inbred mice to retroviral infections make the mouse an excellent model for mapping mammalian susceptibility/resistance genes. Mouse Mammary Tumor Virus (MMTV) and Murine Leukemia Virus (MuLV) are retroviruses that are not efficiently eliminated by the immune system of susceptible mouse strains. In contrast, 1/LnJ mice infected with either virus are capable of producing lgG2a virus-neutralizing antibodies, sustain this response throughout their life, and prevent infection of the progeny by coating secreted virions with anti-virus antibodies. Although an initial polyisotypic anti-virus immune response was observed in susceptible mice it was short-lived and did not class switch to the lgG2a specific response as it did in resistant ILn/J mice. We established that antibody-mediated interference with viral entry into host cells is the sole factor inhibiting virus replication in 1/LnJ mice. Further investigation revealed that IFN-y-producing CD4+ T cells were absolutely indispensable for the virus resistance in 1/LnJ mice. IFN-y signaling induces a number of immune response-related genes which play a vital role in eradication of pathogens. However, it also stimulates expression of its own inhibitor, suppressor of cytokine signaling 1 (SOCS1). We found that cells from susceptible mice produced high levels of IFN-yand up-regulated SOCS1 expression in response to retroviruses. In drastic contrast, resistant l/LnJ mice produced significantly less virally-elicited IFN-y resulting in a weak up-regulation of SOCS1 expression that was insufficient to suppress the IFN-y signaling. We hypothesize that low, but persistent production of IFN-y, that is uninhibited by a negative regulatory mechanism, results in a steady anti-retroviral immune response in 1/LnJ mice. A genetic approach allowed us to establish that anti-virus immunity in l/LnJ mice is influenced by two recessive genes (virus infectivity controller 1 or vid) and vic2 mapped to Chromosome 17 and 15, respectively. Unlike l/LnJ mice, susceptible C3H/HeN mice inherit the dominant allele of the vie genes, which do not allow an anti-virus immune response. We hypothesize that the vie genes monitor the levels of I FN-y production in response to retroviruses and subsequently control anti-virus immunity. The elucidation of the mechanism of resistance in l/LnJ mice is of fundamental importance and will ultimately lead to increased knowledge about variations in susceptibility to viral infections in humans and to development of the most effective vaccines against human viruses, and other diseases.

逆转录病毒通过破坏宿主的免疫反应在人类中引起致命的疾病。虽然研究在人群中遗传对逆转录病毒的抗性是非常困难的，近交系小鼠对逆转录病毒感染的易感性使其成为一种极好的作图模型哺乳动物易感性/抗性基因。小鼠乳腺肿瘤病毒（MMTV）与小鼠白血病病毒（MuLV）是不能被易感小鼠的免疫系统有效清除的逆转录病毒菌株相比之下，感染任何一种病毒的1/LnJ小鼠都能够产生中和病毒的lgG 2a 抗体，维持这种反应在其整个生命，并防止感染的后代，分泌出带有抗病毒抗体的病毒体虽然最初的多同型抗病毒免疫应答是在易感小鼠中观察到，它是短暂的，并且没有类别转换到IgG 2a特异性应答，因为它在耐药ILn/J小鼠中。我们确定抗体介导的干扰病毒进入宿主细胞是1/LnJ小鼠中抑制病毒复制的唯一因子。进一步的研究表明，IFN-γ产生 CD 4 + T细胞是1/LnJ小鼠抵抗病毒感染所必需的。IFN-γ信号转导诱导许多免疫应答相关基因在消灭病原体中起着至关重要的作用。但还刺激其自身抑制剂、细胞因子信号转导抑制因子1（SOCS 1）的表达。我们发现来自易感小鼠的细胞产生高水平的IFN-γ，并上调SOCS 1的表达，逆转录病毒。与此形成鲜明对比的是，抗性l/LnJ小鼠产生显著较少的病毒诱导的IFN-γ。导致SOCS 1表达的微弱上调，其不足以抑制IFN-γ信号传导。我们假设，低，但持续生产的IFN-γ，这是不受抑制的负调控，机制，在1/LnJ小鼠中产生稳定的抗逆转录病毒免疫应答。遗传学方法使我们能够确定l/LnJ小鼠的抗病毒免疫力受两个因素的影响，隐性基因（病毒感染性控制子1或vid）和vic 2定位于染色体17和15，分别与I/LnJ小鼠不同，易感的C3 H/HeN小鼠遗传了vie基因的显性等位基因，它们不允许抗病毒免疫应答。我们假设vie基因监控着 IFN-γ的产生响应于逆转录病毒，并随后控制抗病毒免疫。阐明l/LnJ小鼠的耐药机制具有根本的重要性，最终导致对人类病毒感染易感性变化的了解增加，开发针对人类病毒和其他疾病的最有效疫苗。