MCV-miR-M1 Targets the Host-Cell Immune Response Resulting in the Attenuation of Neutrophil Chemotaxis
MCV-miR-M1 Targets the Host-Cell Immune Response Resulting in the Attenuation of Neutrophil Chemotaxis
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DOI：
10.1016/j.jid.2018.03.1527
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发表时间：
2018-11-01
影响因子：
6.5
通讯作者：
Boyne, James R.
中科院分区：
文献类型：
--
作者：
Akhbari, Pouria;Tobin, Desmond;Boyne, James R.
病毒编码的microRNA正在成为持续感染和宿主细胞免疫逃避的关键调节因子。默克尔细胞多瘤病毒是默克尔细胞癌的主要病原体，其编码单个微小RNA MCV-miR-M1，其靶向致癌的默克尔细胞多瘤病毒大T抗原。MCV-miR-M1以前已被证明在建立长期感染中发挥重要作用，然而，其潜在机制尚未完全了解。一个关键的未回答的问题是，除了自动调节大T抗原，MCV-miR-M1是否也靶向细胞转录物，以协调有利于持续感染的环境。为了解决这个问题，我们采用了基于RNA测序的方法来鉴定MCV-miR-M1的细胞靶点。有趣的是，对表达MCV-miR-M1的细胞中差异表达的转录物的生物信息学分析揭示了与免疫逃避有关的几个基因。随后的靶标验证导致将先天免疫蛋白SP100鉴定为MCV-miR-M1的直接靶标。此外，MCV-miR-M1介导的SP100调节与CXCL 8分泌的显著减少相关，导致中性粒细胞对携带合成默克尔细胞多瘤病毒的默克尔细胞的趋化性减弱。基于这些观察结果，我们提出MCV-miR-M1靶向关键的免疫反应调节因子，以帮助促进持续感染，这是默克尔细胞癌细胞转化的先决条件。
Virus-encoded microRNAs are emerging as key regulators of persistent infection and host-cell immune evasion. Merkel cell polyomavirus, the predominant etiological agent of Merkel cell carcinoma, encodes a single microRNA, MCV-miR-M1, which targets the oncogenic Merkel cell polyomavirus large T antigen. MCV-miR-M1 has previously been shown to play an important role in the establishment of long-term infection, however, the underlying mechanism is not fully understood. A key unanswered question is whether, in addition to autoregulating large T antigen, MCV-miR-M1 also targets cellular transcripts to orchestrate an environment conducive to persistent infection. To address this, we adopted an RNA sequencing-based approach to identify cellular targets of MCV-miR-M1. Intriguingly, bioinformatics analysis of transcripts that are differentially expressed in cells expressing MCV-miR-M1 revealed several genes implicated in immune evasion. Subsequent target validation led to the identification of the innate immunity protein, SP100, as a direct target of MCV-miR-M1. Moreover, MCV-miR-M1-mediated modulation of SP100 was associated with a significant decrease in CXCL8 secretion, resulting in the attenuation of neutrophil chemotaxis toward Merkel cells harboring synthetic Merkel cell polyomavirus. Based on these observations, we propose that MCV-miR-M1 targets key immune response regulators to help facilitate persistent infection, which is a prerequisite for cellular transformation in Merkel cell carcinoma.