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 5

Restriction of CHIKV replication in skeletal muscle diminishes interosseous muscle inflammation and necrosis.

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Restriction of CHIKV replication in skeletal muscle diminishes interosse...
Three- to 4-week-old male C57BL/6J mice inoculated in the left rear footpad with PBS (mock) or 103 PFU of WT SL15649, SKE MM, or SKE. (A) H&E staining of left rear interosseous muscle of mock-, SKE MM–, or SKE-infected mice 7 days after inoculation. Data are representative of 2 independent experiments with 3 mice per group in each experiment. Scale bars: 100 μm. (B) H&E-stained sections were scored for histological evidence of synovitis, inflammation, and necrosis in the interosseous muscle, and tenosynovitis. Results are expressed as disease score of tissues from individual animals for 5 to 6 mice per group. Horizontal bars indicate mean disease score. Scores were assigned based on the following scale: 0, no lesions; 1, mild, fewer than 5 areas of small clusters of leukocytes; 2, moderate, leukocytes forming larger clusters to thin tracts throughout the tissue, multiple sites/tissues affected; 3, severe, clusters and tracts of leukocytes coalescing into at least 1 large area that displaces/replaces tissue; 4, markedly severe, leukocytes in aggregates sufficient to replace more than 40% of normal tissue. Error bars indicate SEM. P values were determined by comparing SKE and SKE MM by Mann Whitney test. *P < 0.05; **P < 0.01.