Chikungunya virus replication in skeletal muscle cells is required for disease development
Anthony J. Lentscher, … , Thomas E. Morrison, Terence S. Dermody
Anthony J. Lentscher, … , Thomas E. Morrison, Terence S. Dermody
Published December 3, 2019
Citation Information: J Clin Invest. 2020;130(3):1466-1478. https://doi.org/10.1172/JCI129893.
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Research Article Infectious disease Virology

Chikungunya virus replication in skeletal muscle cells is required for disease development

Abstract

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.

Authors

Anthony J. Lentscher, Mary K. McCarthy, Nicholas A. May, Bennett J. Davenport, Stephanie A. Montgomery, Krishnan Raghunathan, Nicole McAllister, Laurie A. Silva, Thomas E. Morrison, Terence S. Dermody

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Figure 6

CHIKV replication in myofibers promotes T cell infiltration into interosseous muscle.

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CHIKV replication in myofibers promotes T cell infiltration into interos...
Three- to 4-week-old male C57BL/6J mice were inoculated in the left rear footpad with PBS (mock) or 103 PFU of either SKE MM or SKE. Left ankle tissue was collected 7 days after inoculation and processed for either CD3 immunohistochemistry (A) or H&E staining (B). Regions corresponding to high-magnification insets (×10) of the interosseous muscle and calcaneal tendon (connective tissue) are indicated in the overview micrographs (×1) by black boxes. Representative images of 3 (mock and SKE) or 4 (SKE MM) mice per group are shown. Scale bars: ×1, 3 mm; ×10, 300 μm; ×20, 150 μm. Images were acquired using an Aperio ScanScope XT slide scanner and processed with Aperio ImageScope software. DAB signal corresponding to CD3 (C) or CD4 (D) staining in interosseous muscle was quantified using ImageJ software. Horizontal bars indicate mean intensity. Error bars indicate SEM. P values were determined comparing SKE and SKE MM by 2-tailed Student’s t test. *P < 0.05.