Bio-Informatics: Towards Understanding RNA-Viruses

Current Research

RNA viruses, the largest group of viruses, cause many epidemic diseases in the human population, among crops and domestic livestock. These viruses possess enormous potential to evolve quickly, due to low fidelity of viral RNA polymerases and high frequency of recombination. To safeguard human life in a world densely populated by ever-changing viruses, a thorough understanding of relationships among different viruses as well as between viral and cellular components is essential. These relationships must be determined according to their phylogenetic links, physical interactions, and functional interplay. We approach these goals by applying computer methods of comparative sequence analysis and protein structural modeling to RNA viral proteins, their cellular relatives and partners. In recent years, we have focused our efforts on characterizing proteins involved in replication, expression and encapsidation of genomes of diverse double-stranded and positive single-stranded RNA viruses that belong to Alphavirus genus and the Birnaviridae, Flaviviridae, Picornaviridae, Tetraviridae families and, most actively, the Nidovirales order. Models developed in the course of our theoretical analyses have been successfully incorporated in other researchers' studies many of which have been conducted through fruitful collaboration.

Research Topics

• Origin and Evolution of RNA viruses
• Evolution and molecular mechanisms of proteolytic processing in RNA viruses
• SARS coronavirus
• Hunting for new human and other animal RNA viruses
• Software developing for RNA virus genome data management, analysis and integration

People working on the Project

Major Collaborators

·         Dr. B. Canard, Marseille University, Marseille, France (RNA virus proteome)

·         Dr. E. Ehrenfeld, NIH, Bethesda , MD , USA (Picornavirus replication)

·         Dr. K. Kean, Pasteur Inst., Paris , France (Control of protein synthesis)

·         Prof. A.M. Leontovich, Moscow State University , Moscow , Russia (Bioinformatics)

·         Dr. E. Mundt, The University of Georgia, Athens GA , USA (Birnavirus proteome)

·         Prof. S. Siddell, Bristol University , Bristol , G. Britain (Coronavirus genetics)

·         Dr. E. Snijder, LUMC, Leiden , Netherlands (Nidovirus proteome)

·         Prof. W. Spaan, LUMC, Leiden , Netherlands (Virus detection and discovery)

·         Dr. V. Ward, Otaga University , Otaga , New Zealand (Tetraviridae proteome)

·         Prof. E. Wimmer, State Univ. NY , Stony Brook NY, USA (Enterovirus Evolution)

·         Prof. J. Ziebuhr, The Queen's Univ. of Belfast , UK (Nidovirus proteome)

Key Publications

• Le Gall, O., Christian, P., Fauquet, C., King, A., Knowles, N.J., Nakashima, N., Stanway, G., Gorbalenya A.E. (2008) Picornavirales, a proposed order of positive-sense single-stranded RNA viruses with a pseudo T=3 virion architecture. Arch. of Virology, 153: 715-727
• Jiang, P., Faase, J.A.J., Toyoda, H., Paul, A., Wimmer, E., Gorbalenya A.E. (2007) Evidence for emergence of diverse polioviruses from C-cluster coxsackie A viruses and implications for global poliovirus eradication. Proc. Natl. Acad. Sci. USA, 104: 9457-9462.
• Gorbalenya A.E.L., Enjuanes L., Ziebuhr J., Snijder E.J. (2006). Nidovirales: evolving the largest RNA virus genome. Virus Research, 117: 17-37.
• Teterina N., Gorbalenya A.E.L., Egger D., Bienz K., Rinaudo M., Ehrenfeld E. (2006). Testing the modularity of the N-terminal amphipathic helix conserved in picornavirus 2C proteins and hepatitis C NS5a protein. Virology, 344(2), 453-467.
• Imbert I., Guillemot J.C., Bourhis J.M., Bussetta C., Coutard B., Egloff M.P., Ferron F., Gorbalenya A.E., Canard B. (2006) A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus, The EMBO J. 25:4933-4942.
• van Aken D., Snijder E.J., Gorbalenya A.E. (2006) Mutagenesis analysis of the nsp4 main proteinase reveals determinants of arterivirus replicase polyprotein autoprocessing. J. Virol. 80:3428-37. 
• Minskaia E., Hertzig T., Gorbalenya A.E., Campanacci V., Cambillau C., Canard B., Ziebuhr J. (2006) Discovery of an RNA virus 3'->5' exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc. Natl. Acad. Sci. U.S.A. 103: 5108-5113. 
• Seybert A., Posthuma C.C., van Dinten L.C., Snijder E.J., Gorbalenya A.E., Ziebuhr J.  (2005) A complex zinc finger controls the enzymatic activities of nidovirus helicases. J. Virol. 79:696-704. 
• Egloff M.P., Ferron F., Campanacci V., Longhi S., Rancurel C., Dutartre H., Snijder E.J., Gorbalenya A.E., Cambillau C., Canard B. (2004) The severe acute respiratory syndrome-coronavirus replicative protein nsp9 is a single-stranded RNA-binding subunit unique in the RNA virus world. Proc. Natl. Acad. Sci. U.S.A. 101: 3792-3796.
• Ivanov K.A., Hertzig T., Rozanov M., Bayer S., Thiel V., Gorbalenya A.E., Ziebuhr J. (2004) Major genetic marker of nidoviruses encodes a replicative endoribonuclease. Proc. Natl. Acad. Sci. U.S.A. 101:12694-12699.
• Gorbalenya A.E., Snijder E.J., Spaan W.J.M. (2004) Severe Acute Respiratory Syndrome Coronavirus Phylogeny: toward consensus. J. Virol., 78 (15): 7863-7866. 
• Snijder E.J., Bredenbeek P.J., Dobbe J.C., Thiel V., Ziebuhr J., Poon L.L.M., Guan Y., Rozanov M., Spaan W.J.M., Gorbalenya A.E. (2003) Unique and conserved features of genome and proteome of SARS-Coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol, 331(5): 991-1004.
• Gorbalenya A.E., Pringle F.M., Zeddam J.L., Luke B.T., Cameron C.E., Kalmakoff J., Hanzlik T., Gordon K., Ward V.K. (2002) The palm subdomain-based active site is internally permuted in viral RNA-dependent RNA polymerases of an ancient lineage. J Mol Biol 324(1): 47-62.
• Gorbalenya, A. E. (2001). Big nidovirus genome: when count and order of domains matter. Adv. Exp. Med. Biol. 494: 1-17.
• Ziebuhr J., Thiel, V., Gorbalenya A.E. (2001) The autocatalytic release of a putative RNA virus transcription factor from its polyprotein precursor involves two paralogous papain-like proteases that cleave the same peptide bond. J Biol Chem 276(35): 33220-33232.
• Birghan C., Mundt E., Gorbalenya A.E. (2000) A non-canonical Lon proteinase lacking the ATPase domain employs the Ser-Lys catalytic dyad to exercise broad control over the life cycle of a double-stranded RNA virus. The EMBO J 19(1): 114-123.
• Herold J., Siddell S.G., Gorbalenya A.E. (1999) A human RNA viral cysteine proteinase that depends upon a unique Zn⁺⁺-binding finger connecting the two domains of a papain-like fold. J Biol Chem 274 (21): 14918-14925.

A complete overview of publications on this research topic is available in PubMed

Selected Links: Bio-Informatics, RNA-Viruses