Chikungunya virus (CHIKV) is an arbovirus capable of causing a severe and often debilitating rheumatic syndrome in humans. CHIKV replicates in a wide variety of cell types in mammals, which has made attributing pathologic outcomes to replication at specific sites difficult. To assess the contribution of CHIKV replication in skeletal muscle cells to pathogenesis, we engineered a CHIKV strain exhibiting restricted replication in these cells via incorporation of target sequences for skeletal muscle cell–specific miR-206. This virus, which we term SKE, displayed diminished replication in skeletal muscle cells in a mouse model of CHIKV disease. Mice infected with SKE developed less severe disease signs, including diminished swelling in the inoculated foot and less necrosis and inflammation in the interosseous muscles. SKE infection was associated with diminished infiltration of T cells into the interosseous muscle as well as decreased production of Il1b, Il6, Ip10, and Tnfa transcripts. Importantly, blockade of the IL-6 receptor led to diminished swelling of a control CHIKV strain capable of replication in skeletal muscle, reducing swelling to levels observed in mice infected with SKE. These data implicate replication in skeletal muscle cells and release of IL-6 as important mediators of CHIKV disease.

中文翻译：

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基孔肯雅病毒在骨骼肌细胞中复制是疾病发展所必需的


基孔肯雅病毒（CHIKV）是一种虫媒病毒，能够引起人类严重且常常使人衰弱的风湿综合症。 CHIKV 在哺乳动物的多种细胞类型中复制，这使得将病理结果归因于特定位点的复制变得困难。为了评估骨骼肌细胞中 CHIKV 复制对发病机制的贡献，我们通过掺入骨骼肌细胞特异性 miR-206 的靶序列，设计了一种 CHIKV 菌株，该菌株在这些细胞中表现出有限的复制。这种病毒（我们称之为 SKE）在 CHIKV 疾病小鼠模型的骨骼肌细胞中表现出复制减少。感染 SKE 的小鼠出现的疾病症状较轻，包括接种足部肿胀减轻，骨间肌坏死和炎症减轻。 SKE 感染与 T 细胞向骨间肌的浸润减少以及Il1b 、 Il6 、 Ip10和Tnfa转录本的产生减少有关。重要的是，IL-6受体的阻断导致能够在骨骼肌中复制的对照CHIKV毒株的肿胀减少，将肿胀减少到感染SKE的小鼠中观察到的水平。这些数据表明骨骼肌细胞中的复制和 IL-6 的释放是 CHIKV 疾病的重要介质。