MicroRNome analysis unravels the molecular basis of SARS infection in bronchoalveolar stem cells.
MicroRNome analysis unravels the molecular basis of SARS infection in bronchoalveolar stem cells.
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MicroNOME分析揭开了支气管肺泡干细胞中SARS感染的分子基础。
DOI：
10.1371/journal.pone.0007837
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发表时间：
2009-11-13
期刊：
影响因子：
3.7
通讯作者：
Chakrabarti J
中科院分区：
文献类型：
--
作者：
Mallick B;Ghosh Z;Chakrabarti J
严重急性呼吸综合征（severeacuterespiratorysyndrome，SARS）是由冠状病毒SARS-CoV引起的一种急性传染病。与SARS相关的典型临床特征是肺纤维化和相关的肺衰竭。在SARS流行之后，虽然在了解感染的潜在分子机制方面取得了重大进展，但关于SARS-CoV在感染开始时如何与宿主细胞相互作用的知识仍然存在很大的差距。快速变化的病毒基因组给这个等式增加了另一个变量。我们专注于一个新的概念，微RNA（miRNA）介导的宿主病毒相互作用的支气管肺泡干细胞（BASCs）在感染开始时，通过相关的“BASC-microRNome”与它们的目标BASCs和病毒基因组。本工作包括miRNA阵列数据分析、靶点预测和miRNA-mRNA富集分析，并建立了SARS通路中疾病相关因子、miRNA和BASCs之间的复杂相互作用图谱，这将为诊断标志物提供一些线索，以观察导致疾病进展的整体相互作用。我们的观察显示BASCs（Sca-1+ CD 34 + CD 45- Pecam-）是位于支气管肺泡管连接处的Oct-4+ ACE 2+上皮集落细胞的一个亚群，是SARS-CoV感染的主要靶细胞。上调的BASC miRNAs-17*、-574-5p和-214被SARS-CoV吸收以抑制其自身复制并逃避免疫消除，直到成功传播发生。病毒核衣壳和刺突蛋白靶标似乎分别在BASC内协同下调miR-223和miR-98以控制BASC分化的各个阶段、炎性趋化因子的活化和ACE 2的下调。所有这些都有效地解释了BASC内成功的病毒传播和复制，导致肺组织的持续恶化和肺修复能力的明显丧失。总的来说，这项研究揭示了病毒利用细胞miRNA机制的另一种模式。
Severe acute respiratory syndrome (SARS), caused by the coronavirus SARS-CoV, is an acute infectious disease with significant mortality. A typical clinical feature associated with SARS is pulmonary fibrosis and associated lung failure. In the aftermath of the SARS epidemic, although significant progress towards understanding the underlying molecular mechanism of the infection has been made, a large gap still remains in our knowledge regarding how SARS-CoV interacts with the host cell at the onset of infection. The rapidly changing viral genome adds another variable to this equation. We have focused on a novel concept of microRNA (miRNA)–mediated host–virus interactions in bronchoalveolar stem cells (BASCs) at the onset of infection by correlating the “BASC–microRNome” with their targets within BASCs and viral genome. This work encompasses miRNA array data analysis, target prediction, and miRNA–mRNA enrichment analysis and develops a complex interaction map among disease-related factors, miRNAs, and BASCs in SARS pathway, which will provide some clues for diagnostic markers to view an overall interplay leading to disease progression. Our observation reveals the BASCs (Sca-1+ CD34+ CD45- Pecam-), a subset of Oct-4+ ACE2+ epithelial colony cells at the broncho-alveolar duct junction, to be the prime target cells of SARS-CoV infection. Upregulated BASC miRNAs-17*, -574-5p, and -214 are co-opted by SARS-CoV to suppress its own replication and evade immune elimination until successful transmission takes place. Viral Nucleocapsid and Spike protein targets seem to co-opt downregulated miR-223 and miR-98 respectively within BASCs to control the various stages of BASC differentiation, activation of inflammatory chemokines, and downregulation of ACE2. All these effectively accounts for a successful viral transmission and replication within BASCs causing continued deterioration of lung tissues and apparent loss of capacity for lung repair. Overall, this investigation reveals another mode of exploitation of cellular miRNA machinery by virus to their own advantage.
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