Skip to main content
Virologica Sinica logoLink to Virologica Sinica
. 2011 Aug 17;26(4):229. doi: 10.1007/s12250-011-3211-z

Epidemiology and mutational analysis of global strains of crimean-congo haemorrhagic fever virus

Na Han 1, Simon Rayner 1,
PMCID: PMC8222426  PMID: 21847754

Abstract

Crimean-Congo hemorrhagic fever (CCHF) is a severe illness with high fatality. Cases are reported in several countries in Africa, Europe, the Middle East, and Asia. Phylogenetic analyses based on the virus S (nucleocapsid), M (glycoprotein), and L (polymerase) genome segments sequences indicate distinct geographic lineages exist but their specific genetic characteristics require elucidation. In this work we collected all full length S segment sequences and generated a phylogenetic tree based on the alignment of these 62 samples. We then analyzed the alignment using entries from AAIndex, the Amino Acid Index database, to identify amino acid mutations that performed significant changes in charge, pka, hydropathy and side chain volume. Finally, we mapped these changes back to the tree and alignment to identify correlated mutations or sites that characterized a specific lineage. Based on this analysis we are able to propose a number of sites that appear to be important for virus function and which would be good candidates for experimental mutational analysis studies.

Key words: Crimean-Congo hemorrhagic fever virus (CCHFV), Epidemiology, Mutational Analysis

References

  • 1.Albertini A. A., Wernimont A. K., Muziol T., et al. Crystal structure of the rabies virus nucleoprotein-RNA complex. Science. 2006;313:360–363. doi: 10.1126/science.1125280. [DOI] [PubMed] [Google Scholar]
  • 2.Anagnostou V., Papa A. Evolution of Crimean- Congo Hemorrhagic Fever virus. Infect Genet Evol. 2009;9:948–954. doi: 10.1016/j.meegid.2009.06.018. [DOI] [PubMed] [Google Scholar]
  • 3.Aradaib I. E., Erickson B. R., Karsany M. S., et al. Multiple crimean-congo hemorrhagic Fever virus strains are associated with disease outbreaks in Sudan, 2008–2009. PLoS Negl Trop Dis. 2011;5:e1159. doi: 10.1371/journal.pntd.0001159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Aradaib I. E., Erickson B. R., Mustafa M. E., et al. Nosocomial outbreak of Crimean-Congo hemorrhagic fever, Sudan. Emerg Infect Dis. 2010;16:837–839. doi: 10.3201/eid1605.091815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Chinikar S., Persson S. M., Johansson M., et al. Genetic analysis of Crimean-congo hemorrhagic fever virus in Iran. J Med Virol. 2004;73:404–411. doi: 10.1002/jmv.20106. [DOI] [PubMed] [Google Scholar]
  • 6.Drosten C., Minnak D., Emmerich P., et al. Crimean-Congo hemorrhagic fever in Kosovo. J Clin Microbiol. 2002;40:1122–1123. doi: 10.1128/JCM.40.3.1122-1123.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Eifan S. A., Elliott R. M. Mutational analysis of the Bunyamwera orthobunyavirus nucleocapsid protein gene. J Virol. 2009;83:11307–11317. doi: 10.1128/JVI.01460-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Eisenberg D. Three-dimensional structure of membrane and surface proteins. Annu Rev Biochem. 1984;53:595–623. doi: 10.1146/annurev.bi.53.070184.003115. [DOI] [PubMed] [Google Scholar]
  • 9.Elton D., Medcalf E., Bishop K., et al. Oligomerization of the influenza virus nucleoprotein: identification of positive and negative sequence elements. Virology. 1999;260:190–200. doi: 10.1006/viro.1999.9818. [DOI] [PubMed] [Google Scholar]
  • 10.Elton D., Medcalf L., Bishop K., et al. Identification of amino acid residues of influenza virus nucleoprotein essential for RNA binding. J Virol. 1999;73:7357–7367. doi: 10.1128/jvi.73.9.7357-7367.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Fauchere J. L., Charton M., Kier L. B., et al. Amino acid side chain parameters for correlation studies in biology and pharmacology. Int J Pept Protein Res. 1988;32:269–278. doi: 10.1111/j.1399-3011.1988.tb01261.x. [DOI] [PubMed] [Google Scholar]
  • 12.Gao X., Nasci R., Liang G. The neglected arboviral infections in mainland China. PLoS Negl Trop Dis. 2010;4:e624. doi: 10.1371/journal.pntd.0000624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Gargili A., Midilli K., Ergonul O., et al. Crimean-congo hemorrhagic Fever in European part of Turkey: genetic analysis of the virus strains from ticks and a seroepidemiological study in humans. Vector Borne Zoonotic Dis. 2011;11:747–752. doi: 10.1089/vbz.2010.0030. [DOI] [PubMed] [Google Scholar]
  • 14.Goldsack D. E., Chalifoux R. C. Contribution of the free energy of mixing of hydrophobic side chains to the stability of the tertiary structure of proteins. J Theor Biol. 1973;39:645–651. doi: 10.1016/0022-5193(73)90075-1. [DOI] [PubMed] [Google Scholar]
  • 15.Hewson R., Chamberlain J., Mioulet V., et al. Crimean-Congo haemorrhagic fever virus: sequence analysis of the small RNA segments from a collection of viruses world wide. Virus Res. 2004;102:185–189. doi: 10.1016/j.virusres.2003.12.035. [DOI] [PubMed] [Google Scholar]
  • 16.Hoogstraal H. The epidemiology of tick-borne Crimean-Congo hemorrhagic fever in Asia, Europe, and Africa. J Med Entomol. 1979;15:307–417. doi: 10.1093/jmedent/15.4.307. [DOI] [PubMed] [Google Scholar]
  • 17.Kawashima S., Pokarowski P., Pokarowska M., et al. AAindex: amino acid index database, progress report 2008. Nucl Acids Res. 2008;36:D202–205. doi: 10.1093/nar/gkm998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Krigbaum W. R., Komoriya A. Local interactions as a structure determinant for protein molecules: II. Biochim Biophys Acta. 1979;576:204–248. doi: 10.1016/0005-2795(79)90498-7. [DOI] [PubMed] [Google Scholar]
  • 19.Kuhn J. H., Seregin S. V., Morzunov S. P., et al. Genetic analysis of the M RNA segment of Crimean-Congo hemorrhagic fever virus strains involved in the recent outbreaks in Russia. Arch Virol. 2004;149:2199–2213. doi: 10.1007/s00705-004-0354-3. [DOI] [PubMed] [Google Scholar]
  • 20.Longhi S. Nucleocapsid structure and function. Curr Top Microbiol Immunol. 2009;329:103–128. doi: 10.1007/978-3-540-70523-9_6. [DOI] [PubMed] [Google Scholar]
  • 21.Meissner J. D., Seregin S. S., Seregin S. V., et al. A variable region in the Crimean-Congo hemorrhagic fever virus L segment distinguishes between strains isolated from different geographic regions. J Med Virol. 2006;78:223–228. doi: 10.1002/jmv.20531. [DOI] [PubMed] [Google Scholar]
  • 22.Midilli K., Gargili A., Ergonul O., et al. Imported Crimean-Congo hemorrhagic fever cases in Istanbul. BMC Infect Dis. 2007;7:54. doi: 10.1186/1471-2334-7-54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Mild M., Simon M., Albert J., et al. Towards an understanding of the migration of Crimean-Congo hemorrhagic fever virus. J Gen Virol. 2010;91:199–207. doi: 10.1099/vir.0.014878-0. [DOI] [PubMed] [Google Scholar]
  • 24.Mir M. A., Panganiban A. T. The hantavirus nucleocapsid protein recognizes specific features of the viral RNA panhandle and is altered in conformation upon RNA binding. J Virol. 2005;79:1824–1835. doi: 10.1128/JVI.79.3.1824-1835.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Mohl B. P., Barr J. N. Investigating the specificity and stoichiometry of RNA binding by the nucleocapsid protein of Bunyamwera virus. RNA. 2009;15:391–399. doi: 10.1261/rna.1367209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Papa A., Velo E., Papadimitriou E., et al. Ecology of the Crimean-Congo hemorrhagic fever endemic area in Albania. Vector Borne Zoonotic Dis. 2009;9:713–716. doi: 10.1089/vbz.2008.0141. [DOI] [PubMed] [Google Scholar]
  • 27.Roseman M. A. Hydrophilicity of polar amino acid side-chains is markedly reduced by flanking peptide bonds. J Mol Biol. 1988;200:513–522. doi: 10.1016/0022-2836(88)90540-2. [DOI] [PubMed] [Google Scholar]
  • 28.Sun S., Dai X., Aishan M., et al. Epidemiology and phylogenetic analysis of crimean-congo hemorrhagic fever viruses in xinjiang, china. J Clin Microbiol. 2009;47:2536–2543. doi: 10.1128/JCM.00265-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Tahmasebi F., Ghiasi S. M., Mostafavi E., et al. Molecular epidemiology of Crimean- Congo hemorrhagic fever virus genome isolated from ticks of Hamadan province of Iran. J Vector Borne Dis. 2010;47:211–216. [PubMed] [Google Scholar]
  • 30.Tamura K, Peterson D, Peterson N, et al. 2011. MEGA5: Molecular Evolutionary Genetics Analysis using Maximum Likelihood, Evolutionary Distance, and Maximum Parsimony Methods. Mol Biol Evol. 2011 May 4. [Epub ahead of print]. [DOI] [PMC free article] [PubMed]
  • 31.Terribilini M., Lee J. H., Yan C., et al. Prediction of RNA binding sites in proteins from amino acid sequence. RNA. 2006;12:1450–1462. doi: 10.1261/rna.2197306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Thompson J. D., Higgins D. G., Gibson T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucl Acids Res. 1994;22:4673–4680. doi: 10.1093/nar/22.22.4673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Tonbak S., Aktas M., Altay K., et al. Crimean-Congo hemorrhagic fever virus: genetic analysis and tick survey in Turkey. J Clin Microbiol. 2006;44:4120–4124. doi: 10.1128/JCM.00644-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Tsai J., Taylor R., Chothia C., et al. The packing density in proteins: standard radii and volumes. J Mol Biol. 1999;290:253–266. doi: 10.1006/jmbi.1999.2829. [DOI] [PubMed] [Google Scholar]
  • 35.Walter C. T., Bento D. F., Alonso A. G., et al. Amino acid changes within the Bunyamwera virus nucleocapsid protein differentially affect the mRNA transcription and RNA replication activities of assembled ribonucleoprotein templates. J Gen Virol. 2011;92:80–84. doi: 10.1099/vir.0.024240-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Xia H., Li P., Yang J., et al. Epidemiological survey of Crimean-Congo hemorrhagic fever virus in Yunnan, China, 2008. Int J Infect Dis. 2011;15:e459–463. doi: 10.1016/j.ijid.2011.03.013. [DOI] [PubMed] [Google Scholar]
  • 37.Yashina L., Vyshemirskii O., Seregin S., et al. Genetic analysis of Crimean-Congo hemorrhagic fever virus in Russia. J Clin Microbiol. 2003;41:860–862. doi: 10.1128/JCM.41.2.860-862.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Ye Q., Krug R. M., Tao Y. J. The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature. 2006;444:1078–1082. doi: 10.1038/nature05379. [DOI] [PubMed] [Google Scholar]

Articles from Virologica Sinica are provided here courtesy of Wuhan Institute of Virology, Chinese Academy of Sciences

RESOURCES