State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.
Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, China.
PLoS Pathog. 2022 Oct 10;18(10):e1010820. doi: 10.1371/journal.ppat.1010820. eCollection 2022 Oct.
Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating diseases affecting the swine industry worldwide. To investigate the role of miRNAs in the infection and susceptibility of PRRS virus (PRRSV), twenty-four miRNA libraries were constructed and sequenced from PRRSV-infected and mock-infected Porcine alveolar macrophages (PAMs) of Meishan, Landrace, Pietrain and Qingping pigs at 9 hours post infection (hpi), 36 hpi, and 60 hpi. The let-7 family miRNAs were significantly differentially expressed between PRRSV-infected and mock-infected PAMs from 4 pig breeds. The let-7 family miRNAs could significantly inhibit PRRSV-2 replication by directly targeting the 3'UTR of the PRRSV-2 genome and porcine IL6, which plays an important role in PRRSV replication and lung injury. NEAT1 acts as a competing endogenous lncRNA (ceRNA) to upregulate IL6 by attaching let-7 in PAMs. EMSA and ChIP results confirmed that ARID3A could bind to the promoter region of pri-let-7a/let-7f/let-7d gene cluster and inhibit the expression of the let-7 family. Moreover, the NF-κB signaling pathway inhibits the expression of the let-7 family by affecting the nuclear import of ARID3A. The pEGFP-N1-let-7 significantly reduced viral infections and pathological changes in PRRSV-infected piglets. Taken together, NEAT1/ARID3A/let-7/IL6 play significant roles in PRRSV-2 infection and may be promising therapeutic targets for PRRS.
猪繁殖与呼吸综合征（PRRS）是全球范围内影响养猪业的最具经济破坏性疾病之一。为了研究 microRNA（miRNA）在猪繁殖与呼吸综合征病毒（PRRSV）感染和易感性中的作用，我们从梅山、长白、皮特兰和清平猪的肺泡巨噬细胞（PAMs）中构建并测序了 24 个 miRNA 文库，这些细胞分别在感染 PRRSV 和模拟感染 9 小时后（hpi）、36 hpi 和 60 hpi。与 mock 感染的 PAMs 相比，来自 4 个猪品种的 PRRSV 感染的 PAMs 中 let-7 家族 miRNA 表达显著不同。let-7 家族 miRNA 可以通过直接靶向 PRRSV-2 基因组和猪白细胞介素 6（IL6）的 3'UTR 显著抑制 PRRSV-2 复制，而 IL6 在 PRRSV 复制和肺损伤中起着重要作用。NEAT1 作为竞争性内源性 RNA（ceRNA），通过在 PAMs 中结合 let-7 来上调 IL6。EMSA 和 ChIP 结果证实，ARID3A 可以结合 pri-let-7a/let-7f/let-7d 基因簇的启动子区域并抑制 let-7 家族的表达。此外，NF-κB 信号通路通过影响 ARID3A 的核内输入来抑制 let-7 家族的表达。pEGFP-N1-let-7 显著降低了 PRRSV 感染仔猪的病毒感染和病理变化。综上所述，NEAT1/ARID3A/let-7/IL6 在 PRRSV-2 感染中发挥重要作用，可能是 PRRS 的有前途的治疗靶点。
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