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 8

IL-6 mediates CHIKV-induced inflammation.

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IL-6 mediates CHIKV-induced inflammation. Three- to 4-week-old male C57B...
Three- to 4-week-old male C57BL/6J mice were inoculated intraperitoneally with 200 μg of either a monoclonal anti–IL-6 receptor antibody (clone 15A7) or an IgG2b isotype control antibody (clone LTF-2) on days 0, 3, and 5 after inoculation with 103 PFU of either SKE MM or SKE. (A) Swelling of the left rear footpad was quantified using digital calipers on the days shown. Results are normalized to initial footpad area and presented as the mean percentage of initial footpad area for 10 mice per group (SKE MM + isotype and SKE MM + αIL6R) or 5 mice per group (SKE + isotype). Error bars indicate SEM. P values were determined by comparing SKE MM–infected animals receiving IL6R antibody or isotype control by ANOVA followed by Tukey’s post hoc test. *P < 0.05; ****P < 0.0001. (B) Viral loads in day 7 tissue homogenates were determined by RT-qPCR. Horizontal bars indicate mean CHIKV genome copies/μg RNA of 10 mice per group (SKE MM + isotype and SKE MM + αIL6R) or 5 mice per group (SKE + isotype). Error bars indicate SEM. Dashed line indicates limit of detection. P values were determined by comparing SKE MM–infected animals receiving IL6R antibody and SKE MM–infected animals receiving isotype control by ANOVA followed by Tukey’s post hoc test. None of the differences are statistically significant.