Inhibition of type Interferon production by murine leukemia retrovirus (MuLV)

鼠白血病逆转录病毒 (MuLV) 对 1 型干扰素产生的抑制

• 批准号: 318291020
• 负责人: Professor Dr. Stefan Bauer
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318291020?language=en
• 关键词: Inhibition; type; Interferon; production; murine

The innate immune system senses viral RNA via various pattern recognition receptors such as Toll-like receptors (TLR) and RIG-I like helicases (RLH) leading to subsequent immune activation and antiviral type I interferon production. RNA modifications such as 2-O-methylation or N6-methyladenosine (m6A) antagonize or negatively modulate TLR-mediated RNA recognition and may serve as immune evasion strategies for viruses. Importantly, murine leukemia virus particles or isolated genomic RNA will not stimulate murine or human plasmacytoid dendritic cells (pDCs) to produce IFN-alpha. This proposal addresses the potential role of RNA modifications in the modulation of TLR-mediated retroviral RNA recognition. Especially the role of genomic m6A methylation or 2-O-methylation of host cell-derived transfer RNA (tRNA) that is packed into viral particles and serves as primer for reverse transcription will be investigated. MuLV may also affect IFN-alpha production on an additional level, since we have observed that coincubation of MuLV with stimulating TLR ligands such as CpG-DNA leads to inhibition of IFN-alpha production in pDCs. The molecular mechanism of this inhibition will be analyzed in detail. Overall, this analysis will provide a more sophisticated understanding of the immune response to retroviruses and may lead to new approaches for antiviral drug development.

先天免疫系统通过各种模式识别受体（如toll样受体（TLR）和RIG-I样解旋酶（RLH））感知病毒RNA，导致随后的免疫激活和抗病毒I型干扰素的产生。RNA修饰如2- o -甲基化或n6 -甲基腺苷（m6A）可拮抗或负调节tlr介导的RNA识别，并可能作为病毒的免疫逃避策略。重要的是，小鼠白血病病毒颗粒或分离的基因组RNA不会刺激小鼠或人类浆细胞样树突状细胞（pDCs）产生ifn - α。这一建议解决了RNA修饰在tlr介导的逆转录病毒RNA识别的调节中的潜在作用。特别是宿主细胞来源的转移RNA （tRNA）的基因组m6A甲基化或2- o甲基化的作用将被研究，tRNA被包装到病毒颗粒中并作为逆转录的引物。MuLV还可能在额外的水平上影响ifn - α的产生，因为我们已经观察到MuLV与刺激性TLR配体（如CpG-DNA）共孵育导致pDCs中ifn - α的产生受到抑制。本文将详细分析这种抑制作用的分子机制。总的来说，这一分析将提供对逆转录病毒免疫反应的更复杂的理解，并可能导致抗病毒药物开发的新方法。