• 1.

    Ozden S et al., 2007. Human muscle satellite cells as targets of Chikungunya virus infection. PLoS One 2: e527.

  • 2.

    Obeyesekere I, Hermon Y, 1972. Myocarditis and cardiomyopathy after arbovirus infections (dengue and Chikungunya fever). Br Heart J 34: 821827.

    • Search Google Scholar
    • Export Citation
  • 3.

    Obeyesekere I, Hermon Y, 1973. Arbovirus heart disease: myocarditis and cardiomyopathy following dengue and Chikungunya fever–a follow-up study. Am Heart J 85: 186194.

    • Search Google Scholar
    • Export Citation
  • 4.

    Lima STS et al., 2020. Fatal outcome of Chikungunya virus infection in Brazil. Clin Infect Dis. doi: 10.1093/cid/ciaa1038.

  • 5.

    Freitas ARR, Donalisio MR, Alarcón-Elbal PM, 2018. Excess mortality and causes associated with Chikungunya, Puerto Rico, 2014–2015. Emerg Infect Dis 24: 23522355.

    • Search Google Scholar
    • Export Citation
  • 6.

    Hidalgo-Zambrano DM, Jiménez-Canizales CE, Alzate-Piedrahita JA, Medina-Gaitán DA, Rodriguez-Morales AJ, 2016. Electrocardiographic changes in patients with Chikungunya fever. Rev Panam Infecto 18: 1315.

    • Search Google Scholar
    • Export Citation
  • 7.

    Villamil-Gomez WE, Ramirez-Vallejo E, Cardona-Ospina JA, Silvera LA, Rodriguez-Morales AJ, 2016. Electrocardiographic alterations in patients with chikungunya fever from Sucre, Colombia: a 42-case series. Travel Med Infect Dis 14: 510512.

    • Search Google Scholar
    • Export Citation
  • 8.

    Simon F, Paule P, Oliver M, 2008. Chikungunya virus-induced myopericarditis: toward an increase of dilated cardiomyopathy in countries with epidemics? Am J Trop Med Hyg 78: 212213.

    • Search Google Scholar
    • Export Citation
  • 9.

    Economopoulou A, Dominguez M, Helynck B, Sissoko D, Wichmann O, Quenel P, Germonneau P, Quatresous I, 2009. Atypical Chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005–2006 outbreak on Reunion. Epidemiol Infect 137: 534541.

    • Search Google Scholar
    • Export Citation
  • 10.

    Langsjoen RM, Muruato AE, Kunkel SR, Jaworski E, Routh A, 2020. Differential alphavirus defective RNA diversity between intracellular and extracellular compartments is driven by subgenomic recombination events. MBio 11: e0073120.

    • Search Google Scholar
    • Export Citation
  • 11.

    Routh A, Head SR, Ordoukhanian P, Johnson JE, 2015. ClickSeq: fragmentation-free next-generation sequencing via click ligation of adaptors to stochastically terminated 3′-Azido cDNAs. J Mol Biol 427: 26102616.

    • Search Google Scholar
    • Export Citation
  • 12.

    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Subgroup GPDP, 2009. The sequence alignment/map format and SAMtools. Bioinformatics 25: 20782079.

    • Search Google Scholar
    • Export Citation
  • 13.

    Routh A, Ji P, Jaworski E, Xia Z, Li W, Wagner EJ, 2017. Poly(A)-ClickSeq: click-chemistry for next-generation 3′-end sequencing without RNA enrichment or fragmentation. Nucleic Acids Res 45: e112.

    • Search Google Scholar
    • Export Citation
  • 14.

    Routh A, 2019. DPAC: a tool for differential poly(A) cluster usage from poly(A)-targeted RNAseq data. G3 (Bethesda) 9: 18251830.

  • 15.

    Love MI, Huber W, Anders S, 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15: 550.

  • 16.

    Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, Clark NR, Ma’ayan A, 2013. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14: 128.

    • Search Google Scholar
    • Export Citation
  • 17.

    Kuleshov MV et al., 2016. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44: W907.

  • 18.

    Maere S, Heymans K, Kuiper M, 2005. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21: 34483449.

    • Search Google Scholar
    • Export Citation
  • 19.

    Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T, 2003. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13: 24982504.

    • Search Google Scholar
    • Export Citation
  • 20.

    Medeiros-Domingo A et al., 2007. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation 116: 134142.

  • 21.

    Christensen AH et al., 2016. The two-pore domain potassium channel, TWIK-1, has a role in the regulation of heart rate and atrial size. J Mol Cell Cardiol 97: 2435.

    • Search Google Scholar
    • Export Citation
  • 22.

    Hyde JL, Chen R, Trobaugh DW, Diamond MS, Weaver SC, Klimstra WB, Wilusz J, 2015. The 5′ and 3′ ends of alphavirus RNAs–non-coding is not non-functional. Virus Res 206: 99107.

    • Search Google Scholar
    • Export Citation
  • 23.

    Chen R, Wang E, Tsetsarkin KA, Weaver SC, 2013. Chikungunya virus 3′ untranslated region: adaptation to mosquitoes and a population bottleneck as major evolutionary forces. PLoS Pathog 9: e1003591.

    • Search Google Scholar
    • Export Citation
  • 24.

    Stapleford KA et al., 2016. Whole-genome sequencing analysis from the Chikungunya virus caribbean outbreak reveals novel evolutionary genomic elements. PLoS Negl Trop Dis 10: e0004402.

    • Search Google Scholar
    • Export Citation
  • 25.

    Chen R, Puri V, Fedorova N, Lin D, Hari KL, Jain R, Rodas JD, Das SR, Shabman RS, Weaver SC, 2016. Comprehensive genome scale phylogenetic study provides new insights on the global expansion of Chikungunya virus. J Virol 90: 1060010611.

    • Search Google Scholar
    • Export Citation
  • 26.

    Filomatori CV, Bardossy ES, Merwaiss F, Suzuki Y, Henrion A, Saleh MC, Alvarez DE, 2019. RNA recombination at Chikungunya virus 3′UTR as an evolutionary mechanism that provides adaptability. PLoS Pathog 15: e1007706.

    • Search Google Scholar
    • Export Citation
  • 27.

    Grant AO, 2009. Cardiac ion channels. Circ Arrhythm Electrophysiol 2: 185194.

  • 28.

    Lehman W, Craig R, Vibert P, 1994. Ca(2+)-induced tropomyosin movement in Limulus thin filaments revealed by three-dimensional reconstruction. Nature 368: 6567.

    • Search Google Scholar
    • Export Citation
  • 29.

    Affolter H, Chiesi M, Dabrowska R, Carafoli E, 1976. Calcium regulation in heart cells. The interaction of mitochondrial and sarcoplasmic reticulum with troponin-bound calcium. Eur J Biochem 67: 389396.

    • Search Google Scholar
    • Export Citation
 
 

 

 

 

 

 

 

Chikungunya Virus Infects the Heart and Induces Heart-Specific Transcriptional Changes in an Immunodeficient Mouse Model of Infection

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  • 1 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas;
  • | 2 Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, Texas;
  • | 3 Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas

ABSTRACT.

Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen in family Togaviridae, genus Alphavirus. Although CHIKV is well known for its ability to cause debilitating rheumatoid-like arthritis, it has been also been observed to cause cardiovascular symptoms such as arrhythmias. Here, using samples from a previous study, we sequenced RNA from serum, kidney, skeletal muscle, and cardiac muscle from CHIKV- and mock-infected IFN-αR−/− mice using two sequencing techniques to investigate heart-specific changes in virus mutational profiles and host gene expression. Mutation rates were similar across muscle tissues although heart tissue carried heart-specific CHIKV minority variants, one of which had a coding change in the nsP3 gene and another in the 3′UTR. Importantly, heart-specific transcriptional changes included differential expression of genes critical for ion transport and muscle contraction. These results demonstrate that CHIKV replicates in the hearts of immunodeficient mice and induce heart-specific mutations and host responses with implications for cardiac pathologies.

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Author Notes

Address correspondence to Rose M. Langsjoen, Emory University School of Medicine, Department of Pathology, Woodruff Memorial Research Building 7207A, 101 Woodruff Cir NE, Atlanta, GA 30322. E-mail: rlangsj@emory.edu

These authors contributed equally to this work.

Financial support: This study was conducted with the support of the Institute for Translational Sciences at the University of Texas Medical Branch, supported in part by a Clinical and Translational Science Award NRSA (TL1) Training Core (TL1TR001440) from the National Center for Advancing Translational Sciences, National Institutes of Health. R. M. L. was additionally supported by the Jeanne B. Kempner postdoctoral fellowship through the University of Texas Medical Branch, Galveston. Funding for sequencing was provided by start-up funds from the University of Texas Medical Branch.

Authors’ addresses: Rose M. Langsjoen, Yiyang Zhou, and Richard J. Holcomb, University of Texas Medical Branch, Galveston, TX, E-mails: rlangsj@emory.edu, yizhou@utmb.edu, and rjholcom@utmb.edu. Andrew L. Routh, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX, and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, E-mail: alrouth@utmb.edu.

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