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

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）感测病毒RNA，导致随后的免疫激活和抗病毒I型干扰素产生。RNA修饰如2-O-甲基化或N6-甲基腺苷（m6A）拮抗或负调节TLR介导的RNA识别，并可作为病毒的免疫逃避策略。重要的是，鼠白血病病毒颗粒或分离的基因组RNA不会刺激鼠或人浆细胞样树突状细胞（pDC）产生IFN-α。该提议解决了RNA修饰在TLR介导的逆转录病毒RNA识别的调制中的潜在作用。特别是将研究基因组m6A甲基化或宿主细胞来源的转运RNA（tRNA）的2-O-甲基化的作用，所述转运RNA被包装到病毒颗粒中并用作逆转录的引物。MuLV还可以在另外的水平上影响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的共孵育导致pDC中IFN-α产生的抑制。本文将详细分析这种抑制作用的分子机制。总的来说，这项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。

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.