In-vivo-tracking, immune control and autoimmunity in genetic models of murine endogenous retrovirus reactivation

小鼠内源性逆转录病毒再激活遗传模型中的体内追踪、免疫控制和自身免疫

• 批准号: 258301698
• 负责人: Dr. Philipp Yu
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/258301698?language=en
• 关键词: vivo; tracking; immune; control; autoimmunity

HIV is the most infamous new emerging infectious disease in the last decades, still awaiting more effective treatment or successful vaccination. But retroviruses have posed a constant threat to mammals during evolution, culminating in invasion of the human and mouse genome, by so-called endogenous retroviruses (ERVs). Although their functionality as infectious retroviruses is still debated in humans, certain mouse strains can express ERVs, similar to murine leukemia virus (MuLV) and succumb to retrovirus induced disease. Recently, immunologists have demonstrated that both the impairment of adaptive (B cell mediated antibody production) or innate immune recognition (nucleic-acid-sensing TLRs -3,-7 and -9) results in uncontrolled ERV mediated retroviral viremia in murine model systems. However, the complexity of the immune response and potential interactions with a variety of cell intrinsic anti-retroviral mechanism warrant new models deciphering the basics of retroviral expression and immune control. Here, we propose the generation of tagged MuLV, which express fluorescent- or luciferase markers, that allow the in vivo detection of infectious retroviruses or the resurrection of experimentally introduced germline encoded ERVs. These models, in conjunction with the cellular and molecular analysis of ERV recognition and inhibition by innate and adaptive immunity, in particular the B cell response, might allow a better understanding of the biology of retroviral immune interactions in general. Finally, we will try to generate a genetic model, which addresses a mechanism how retroviruses could break self-tolerance and induce autoimmunity in vivo.

艾滋病毒是过去几十年来最臭名昭著的新出现的传染病，仍在等待更有效的治疗或成功的疫苗接种。但是逆转录病毒在进化过程中对哺乳动物构成了持续的威胁，最终导致了所谓的内源性逆转录病毒（ERV）对人类和小鼠基因组的入侵。尽管它们作为感染性逆转录病毒的功能在人类中仍然存在争议，但某些小鼠品系可以表达ERV，类似于鼠白血病病毒（MuLV），并死于逆转录病毒诱导的疾病。最近，免疫学家已经证明，适应性（B细胞介导的抗体产生）或先天性免疫识别（核酸敏感TLR-3、-7和-9）的损伤导致在鼠模型系统中不受控制的ERV介导的逆转录病毒血症。然而，免疫应答的复杂性和与各种细胞内在抗逆转录病毒机制的潜在相互作用保证了新模型破译逆转录病毒表达和免疫控制的基础。在这里，我们提出了标记的MuLV，表达荧光或荧光素酶标记，允许在体内检测感染性逆转录病毒或复活的实验引入的种系编码ERVs的一代。这些模型，与ERV识别和抑制先天性和适应性免疫，特别是B细胞反应的细胞和分子分析相结合，可能会更好地理解一般的逆转录病毒免疫相互作用的生物学。最后，我们将尝试建立一个遗传模型，该模型阐述了逆转录病毒如何打破自身耐受并诱导体内自身免疫的机制。