1887

Abstract

Chikungunya virus (CHIKV), an alphavirus of the family , causes fever, polyarthritis and rash. There are three genotypes: West African, Asian and East/Central/South African (ECSA). The latter two genotypes have caused global outbreaks in recent years. Recent ECSA CHIKV outbreaks have been associated with severe neurological disease, but it is not known if different CHIKV genotypes are associated with different neurovirulence. In this study, the neurovirulence of Asian (MY/06/37348) and ECSA (MY/08/065) strains of CHIKV isolated in Malaysia were compared. Intracerebral inoculation of either virus into suckling mice was followed by virus titration, histopathology and gene expression analysis of the harvested brains. Both strains of CHIKV replicated similarly, yet mice infected with MY/06/37348 showed higher mortality. Histopathology findings showed that both CHIKV strains spread within the brain (where CHIKV antigen was localized to astrocytes and neurons) and beyond to skeletal muscle. In MY/06/37348-infected mice, apoptosis, which is associated with neurovirulence in alphaviruses, was observed earlier in brains. Comparison of gene expression showed that a pro-apoptotic gene (eIF2αK2) was upregulated at higher levels in MY/06/37348-infected mice, while genes involved in anti-apoptosis (BIRC3), antiviral responses and central nervous system protection (including CD40, IL-10RA, MyD88 and PYCARD) were upregulated more highly in MY/08/065-infected mice. In conclusion, the higher mortality observed following MY/06/37348 infection in mice is due not to higher viral replication in the brain, but to differentially expressed genes involved in host immune responses. These findings may help to identify therapeutic strategies and biomarkers for neurological CHIKV infections.

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2015-11-01
2021-07-28
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References

  1. Arpino C., Curatolo P., Rezza G. 2009; Chikungunya and the nervous system: what we do and do not know. Rev Med Virol 19:121–129 [View Article][PubMed]
    [Google Scholar]
  2. Assunção-Miranda I., Cruz-Oliveira C., Da Poian A.T. 2013; Molecular mechanisms involved in the pathogenesis of alphavirus-induced arthritis. BioMed Res Int 2013:973516 [View Article][PubMed]
    [Google Scholar]
  3. Bachis A., Colangelo A.M., Vicini S., Doe P.P., De Bernardi M.A., Brooker G., Mocchetti I. 2001; Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci 21:3104–3112[PubMed]
    [Google Scholar]
  4. Bordignon J., Probst C.M., Mosimann A.L.P., Pavoni D.P., Stella V., Buck G.A., Satproedprai N., Fawcett P., Zanata S.M., other authors. 2008; Expression profile of interferon stimulated genes in central nervous system of mice infected with dengue virus type-1. Virology 377:319–329 [View Article][PubMed]
    [Google Scholar]
  5. Bréhin A.C., Casadémont I., Frenkiel M.P., Julier C., Sakuntabhai A., Desprès P. 2009; The large form of human 2′,5′-oligoadenylate synthetase (OAS3) exerts antiviral effect against Chikungunya virus. Virology 384:216–222 [View Article][PubMed]
    [Google Scholar]
  6. Chen C.-I., Clark D.C., Pesavento P., Lerche N.W., Luciw P.A., Reisen W.K., Brault A.C. 2010; Comparative pathogenesis of epidemic and enzootic Chikungunya viruses in a pregnant Rhesus macaque model. Am J Trop Med Hyg 83:1249–1258 [View Article][PubMed]
    [Google Scholar]
  7. Chiam C.W., Chan Y.F., Loong S.K., Yong S.S.J., Hooi P.S., Sam I.-C. 2013; Real-time polymerase chain reaction for diagnosis and quantitation of negative strand of chikungunya virus. Diagn Microbiol Infect Dis 77:133–137 [View Article][PubMed]
    [Google Scholar]
  8. Chirathaworn C., Rianthavorn P., Wuttirattanakowit N., Poovorawan Y. 2010; Serum IL-18 and IL-18BP levels in patients with Chikungunya virus infection. Viral Immunol 23:113–117 [View Article][PubMed]
    [Google Scholar]
  9. Chow A., Her Z., Ong E.K.S., Chen J.M., Dimatatac F., Kwek D.J.C., Barkham T., Yang H., Rénia L., other authors. 2011; Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. J Infect Dis 203:149–157 [View Article][PubMed]
    [Google Scholar]
  10. Couderc T., Chrétien F., Schilte C., Disson O., Brigitte M., Guivel-Benhassine F., Touret Y., Barau G., Cayet N., other authors. 2008; A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease. PLoS Pathog 4:e29 [View Article][PubMed]
    [Google Scholar]
  11. Das T., Jaffar-Bandjee M.-C., Hoarau J.J., Krejbich Trotot P., Denizot M., Lee-Pat-Yuen G., Sahoo R., Guiraud P., Ramful D., Robin S. 2010; Chikungunya fever: CNS infection and pathologies of a re-emerging arbovirus. Prog Neurobiol 91:121–129 [View Article][PubMed]
    [Google Scholar]
  12. Das T., Hoarau J.J., Jaffar Bandjee M.C., Maquart M., Gasque P. 2015; Multifaceted innate immune responses engaged by astrocytes, microglia and resident dendritic cells against Chikungunya neuroinfection. J Gen Virol 96:294–310 [View Article][PubMed]
    [Google Scholar]
  13. de Kruif M.D., Setiati T.E., Mairuhu A.T.A., Koraka P., Aberson H.A., Spek C.A., Osterhaus A.D.M.E., Reitsma P.H., Brandjes D.P.M., other authors. 2008; Differential gene expression changes in children with severe dengue virus infections. PLoS Negl Trop Dis 2:e215 [View Article][PubMed]
    [Google Scholar]
  14. Dhanwani R., Khan M., Alam S.I., Rao P.V.L., Parida M. 2011; Differential proteome analysis of Chikungunya virus-infected new-born mice tissues reveal implication of stress, inflammatory and apoptotic pathways in disease pathogenesis. Proteomics 11:1936–1951 [View Article][PubMed]
    [Google Scholar]
  15. 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 Réunion. Epidemiol Infect 137:534–541 [View Article][PubMed]
    [Google Scholar]
  16. Fink J., Gu F., Ling L., Tolfvenstam T., Olfat F., Chin K.C., Aw P., George J., Kuznetsov V.A., other authors. 2007; Host gene expression profiling of dengue virus infection in cell lines and patients. PLoS Negl Trop Dis 1:e86 [View Article][PubMed]
    [Google Scholar]
  17. Fros J.J., Liu W.J., Prow N.A., Geertsema C., Ligtenberg M., Vanlandingham D.L., Schnettler E., Vlak J.M., Suhrbier A., other authors. 2010; Chikungunya virus nonstructural protein 2 inhibits type I/II interferon-stimulated JAK-STAT signaling. J Virol 84:10877–10887 [View Article][PubMed]
    [Google Scholar]
  18. Ganesan K., Diwan A., Shankar S.K., Desai S.B., Sainani G.S., Katrak S.M. 2008; Chikungunya encephalomyeloradiculitis: report of 2 cases with neuroimaging and 1 case with autopsy findings. Am J Neuroradiol 29:1636–1637 [View Article][PubMed]
    [Google Scholar]
  19. Gardner J., Anraku I., Le T.T., Larcher T., Major L., Roques P., Schroder W.A., Higgs S., Suhrbier A. 2010; Chikungunya virus arthritis in adult wild-type mice. J Virol 84:8021–8032 [View Article][PubMed]
    [Google Scholar]
  20. Gérardin P., Barau G., Michault A., Bintner M., Randrianaivo H., Choker G., Lenglet Y., Touret Y., Bouveret A., other authors. 2008; Multidisciplinary prospective study of mother-to-child chikungunya virus infections on the island of La Réunion. PLoS Med 5:e60 [View Article][PubMed]
    [Google Scholar]
  21. Griffin D.E. 2005; Neuronal cell death in alphavirus encephalomyelitis. Curr Top Microbiol Immunol 289:57–77[PubMed]
    [Google Scholar]
  22. Gupta N., Rao P.V.L. 2011; Transcriptomic profile of host response in Japanese encephalitis virus infection. Virol J 8:92 [View Article][PubMed]
    [Google Scholar]
  23. Jiang H.-Y., Wek R.C. 2005; Phosphorylation of the α-subunit of the eukaryotic initiation factor-2 (eIF2α) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. J Biol Chem 280:14189–14202 [View Article][PubMed]
    [Google Scholar]
  24. Johnston C., Jiang W., Chu T., Levine B. 2001; Identification of genes involved in the host response to neurovirulent alphavirus infection. J Virol 75:10431–10445 [View Article][PubMed]
    [Google Scholar]
  25. Kam Y.-W., Ong E.K.S., Rénia L., Tong J.-C., Ng L.F.P. 2009; Immuno-biology of Chikungunya and implications for disease intervention. Microbes Infect 11:1186–1196 [View Article][PubMed]
    [Google Scholar]
  26. Koterski J., Twenhafel N., Porter A., Reed D.S., Martino-Catt S., Sobral B., Crasta O., Downey T., DaSilva L. 2007; Gene expression profiling of nonhuman primates exposed to aerosolized Venezuelan equine encephalitis virus. FEMS Immunol Med Microbiol 51:462–472 [View Article][PubMed]
    [Google Scholar]
  27. Krejbich-Trotot P., Denizot M., Hoarau J.J., Jaffar-Bandjee M.C., Das T., Gasque P. 2011; Chikungunya virus mobilizes the apoptotic machinery to invade host cell defenses. FASEB J 25:314–325 [View Article][PubMed]
    [Google Scholar]
  28. Lewis J., Wesselingh S.L., Griffin D.E., Hardwick J.M. 1996; Alphavirus-induced apoptosis in mouse brains correlates with neurovirulence. J Virol 701828–1835[PubMed] Griffin;
    [Google Scholar]
  29. Lohachanakul J., Phuklia W., Thannagith M., Thongsakulprasert T., Smith D.R., Ubol S. 2015; Differences in response of primary human myoblasts to infection with recent epidemic strains of Chikungunya virus isolated from patients with and without myalgia. J Med Virol 87:733–739 [View Article][PubMed]
    [Google Scholar]
  30. McKimmie C.S., Roy D., Forster T., Fazakerley J.K. 2006; Innate immune response gene expression profiles of N9 microglia are pathogen-type specific. J Neuroimmunol 175:128–141 [View Article][PubMed]
    [Google Scholar]
  31. Morris M.M., Dyson H., Baker D., Harbige L.S., Fazakerley J.K., Amor S. 1997; Characterization of the cellular and cytokine response in the central nervous system following Semliki Forest virus infection. J Neuroimmunol 74:185–197 [View Article][PubMed]
    [Google Scholar]
  32. Nimmannitya S., Halstead S.B., Cohen S.N., Margiotta M.R. 1969; Dengue and chikungunya virus infection in man in Thailand, 1962-1964. I. Observations on hospitalized patients with hemorrhagic fever. Am J Trop Med Hyg 18:954–971[PubMed]
    [Google Scholar]
  33. O'Keefe G.M., Nguyen V.T., Benveniste E.N. 2002; Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: implications in neurological diseases. J Neurovirol 8:496–512 [View Article][PubMed]
    [Google Scholar]
  34. Osawa R., Williams K.L., Singh N. 2011; The inflammasome regulatory pathway and infections: role in pathophysiology and clinical implications. J Infect 62:119–129 [View Article][PubMed]
    [Google Scholar]
  35. Ozden S., Huerre M., Riviere J.-P., Coffey L.L., Afonso P.V., Mouly V., de Monredon J., Roger J.-C., El Amrani M., other authors. 2007; Human muscle satellite cells as targets of Chikungunya virus infection. PLoS One 2:e527 [View Article][PubMed]
    [Google Scholar]
  36. Peltier D.C., Lazear H.M., Farmer J.R., Diamond M.S., Miller D.J. 2013; Neurotropic arboviruses induce interferon regulatory factor 3-mediated neuronal responses that are cytoprotective, interferon independent, and inhibited by Western equine encephalitis virus capsid. J Virol 87:1821–1833 [View Article][PubMed]
    [Google Scholar]
  37. Powers A.M., Logue C.H. 2007; Changing patterns of chikungunya virus: re-emergence of a zoonotic arbovirus. J Gen Virol 88:2363–2377 [View Article][PubMed]
    [Google Scholar]
  38. Prosniak M., Hooper D.C., Dietzschold B., Koprowski H. 2001; Effect of rabies virus infection on gene expression in mouse brain. Proc Natl Acad Sci U S A 98:2758–2763 [View Article][PubMed]
    [Google Scholar]
  39. Robin S., Ramful D., Le Seach’ F., Jaffar-Bandjee M.C., Rigou G., Alessandri J.L. 2008; Neurologic manifestations of pediatric chikungunya infection. J Child Neurol 23:1028–1035 [View Article][PubMed]
    [Google Scholar]
  40. Rudd P.A., Wilson J., Gardner J., Larcher T., Babarit C., Le T.T., Anraku I., Kumagai Y., Loo Y.-M., other authors. 2012; Interferon response factors 3 and 7 protect against Chikungunya virus hemorrhagic fever and shock. J Virol 86:9888–9898 [View Article][PubMed]
    [Google Scholar]
  41. Ryman K.D., Klimstra W.B. 2008; Host responses to alphavirus infection. Immunol Rev 225:27–45 [View Article][PubMed]
    [Google Scholar]
  42. Saha S., Rangarajan P.N. 2003; Common host genes are activated in mouse brain by Japanese encephalitis and rabies viruses. J Gen Virol 84:1729–1735 [View Article][PubMed]
    [Google Scholar]
  43. Sam I.C., Chan Y.F., Chan S.Y., Loong S.K., Chin H.K., Hooi P.S., Ganeswrie R., Abubakar S. 2009; Chikungunya virus of Asian and Central/East African genotypes in Malaysia. J Clin Virol 46:180–183 [View Article][PubMed]
    [Google Scholar]
  44. Sam I.C., Loong S.K., Michael J.C., Chua C.L., Wan Sulaiman W.Y., Vythilingam I., Chan S.Y., Chiam C.W., Yeong Y.S., other authors. 2012; Genotypic and phenotypic characterization of Chikungunya virus of different genotypes from Malaysia. PLoS One 7:e50476 [View Article][PubMed]
    [Google Scholar]
  45. Sam I.C., Kümmerer B.M., Chan Y.F., Roques P., Drosten C., AbuBakar S. 2015; Updates on chikungunya epidemiology, clinical disease, and diagnostics. Vector Borne Zoonotic Dis 15:223–230 [View Article][PubMed]
    [Google Scholar]
  46. Sharma A., Maheshwari R.K. 2009; Oligonucleotide array analysis of Toll-like receptors and associated signalling genes in Venezuelan equine encephalitis virus-infected mouse brain. J Gen Virol 90:1836–1847 [View Article][PubMed]
    [Google Scholar]
  47. Sharma A., Bhattacharya B., Puri R.K., Maheshwari R.K. 2008; Venezuelan equine encephalitis virus infection causes modulation of inflammatory and immune response genes in mouse brain. BMC Genomics 9:289 [View Article][PubMed]
    [Google Scholar]
  48. Silverman R.H. 2007; Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J Virol 81:12720–12729 [View Article][PubMed]
    [Google Scholar]
  49. Suthar M.S., Shabman R., Madric K., Lambeth C., Heise M.T. 2005; Identification of adult mouse neurovirulence determinants of the Sindbis virus strain AR86. J Virol 79:4219–4228 [View Article][PubMed]
    [Google Scholar]
  50. Taylor K., Kolokoltsova O., Patterson M., Poussard A., Smith J., Estes D.M., Paessler S. 2012; Natural killer cell mediated pathogenesis determines outcome of central nervous system infection with Venezuelan equine encephalitis virus in C3H/HeN mice. Vaccine 30:4095–4105 [View Article][PubMed]
    [Google Scholar]
  51. Teo T.-H., Her Z., Tan J.J.L., Lum F.-M., Lee W.W.L., Chan Y.-H., Ong R.-Y., Kam Y.-W., Leparc-Goffart I., other authors. 2015; Caribbean and La Réunion chikungunya virus isolates differ in their capacity to induce pro-inflammatory Th1 and NK cell responses and acute joint pathology. J Virol 89:7955–7969 [View Article][PubMed]
    [Google Scholar]
  52. Thon-Hon V.G., Denizot M., Li-Pat-Yuen G., Giry C., Jaffar-Bandjee M.-C., Gasque P. 2012; Deciphering the differential response of two human fibroblast cell lines following Chikungunya virus infection. Virol J 9:213 [View Article][PubMed]
    [Google Scholar]
  53. van de Veerdonk F.L., Netea M.G., Dinarello C.A., Joosten L.A.B. 2011; Inflammasome activation and IL-1β and IL-18 processing during infection. Trends Immunol 32:110–116 [View Article][PubMed]
    [Google Scholar]
  54. van Riel D., Verdijk R., Kuiken T. 2015; The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system. J Pathol 235:277–287 [View Article][PubMed]
    [Google Scholar]
  55. Venter M., Myers T.G., Wilson M.A., Kindt T.J., Paweska J.T., Burt F.J., Leman P.A., Swanepoel R. 2005; Gene expression in mice infected with West Nile virus strains of different neurovirulence. Virology 342:119–140 [View Article][PubMed]
    [Google Scholar]
  56. Voss J.E., Vaney M.C., Duquerroy S., Vonrhein C., Girard-Blanc C., Crublet E., Thompson A., Bricogne G., Rey F.A. 2010; Glycoprotein organization of Chikungunya virus particles revealed by X-ray crystallography. Nature 468:709–712 [View Article][PubMed]
    [Google Scholar]
  57. Wang Z.W., Sarmento L., Wang Y., Li X.-Q., Dhingra V., Tseggai T., Jiang B., Fu Z.F. 2005; Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. J Virol 79:12554–12565 [View Article][PubMed]
    [Google Scholar]
  58. Wang E., Volkova E., Adams A.P., Forrester N., Xiao S.-Y., Frolov I., Weaver S.C. 2008; Chimeric alphavirus vaccine candidates for chikungunya. Vaccine 26:5030–5039 [View Article][PubMed]
    [Google Scholar]
  59. Wang Y., Tang X., Yu B., Gu Y., Yuan Y., Yao D., Ding F., Gu X. 2012; Gene network revealed involvements of Birc2, Birc3 and Tnfrsf1a in anti-apoptosis of injured peripheral nerves. PLoS One 7:e43436 [View Article][PubMed]
    [Google Scholar]
  60. White J.D. 1969; Technical manuscript No. 525. Electron microscopy of chikungunya virus infection in the nervous system of suckling mice. p. 10. Fort Detrick, Maryland, USA: Department of the Army;
    [Google Scholar]
  61. Yang Y., Ye J., Yang X., Jiang R., Chen H., Cao S. 2011; Japanese encephalitis virus infection induces changes of mRNA profile of mouse spleen and brain. Virol J 8:80 [View Article][PubMed]
    [Google Scholar]
  62. Zhou Z., Peng X., Insolera R., Fink D.J., Mata M. 2009; Interleukin-10 provides direct trophic support to neurons. J Neurochem 110:1617–1627 [View Article][PubMed]
    [Google Scholar]
  63. Ziegler S.A., Lu L., da Rosa A.P.A.T., Xiao S.Y., Tesh R.B. 2008; An animal model for studying the pathogenesis of chikungunya virus infection. Am J Trop Med Hyg 79:133–139[PubMed]
    [Google Scholar]
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