Abstract
Ebola hemorrhagic fever (EHF) epidemic currently ongoing in West Africa is not the first among numerous epidemics in the continent. Yet it seems to be the worst EHF epidemic outbreak caused by Ebola virus Zaire since 1976 as regards its extremely large scale and rapid spread in the population. Experiments to study the agent have continued for more than 20 years. The EHF virus has a relatively simple genome with seven genes and additional reading frame resulting from RNA editing. While being of a relatively low genetic capacity, the virus can be ranked as a standard for pathogenicity with the ability to evade the host immune response in uttermost perfection. The EHF virus has similarities with retroviruses, but belongs to (–)RNA viruses of a nonretroviral origin. Genetic elements of the virus, NIRV, were detected in animal and human genomes. EHF virus glycoprotein (GP) is a class I fusion protein and shows more similarities than distinctions in tertiary structure with SIV and HIV gp41 proteins and even influenza virus hemagglutinin. EHF is an unusual infectious disease, and studying the molecular basis of its pathogenesis may contribute to new findings in therapy of severe conditions leading to a fatal outcome.
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Abbreviations
- EHF:
-
Ebola hemorrhagic fever
- DIC:
-
disseminated intravascular coagulation
References
World Health Organization Ebola Response Team. 2014. Ebola virus disease in West Africa: The first 9 months of the epidemic and forward projections. N. Engl. J. Med. 371, 1481–1495.
Gire S.K., Goba A., Andersen K.G., Sealfon R.S., Park D.J., Kanneh L., Jalloh S., Momoh M., Fullah M., Dudas G., Wohl S., Moses L.M., Yozwiak N.L., Winnicki S., Matranga C.B., Malboeuf C.M., Qu J., Gladden A.D., Schaffner S.F., Yang X., Jiang P.P., Nekoui M., Colubri A., Coomber M.R., Fonnie M., Moigboi A., Gbakie M., Kamara F.K., Tucker V., Konuwa E., Saffa S., Sellu J., Jalloh A.A., Kovoma A., Koninga J., Mustapha I., Kargbo K., Foday M., Yillah M., Kanneh F., Robert W., Massally J.L., Chapman S.B., Bochicchio J., Murphy C., Nusbaum C., Young S., Birren B.W., Grant D.S., Scheiffelin J.S., Lander E.S., Happi C., Gevao S.M., Gnirke A., Rambaut A., Garry R.F., Khan S.H., Sabeti P.C. 2014. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science. 345 (6202), 1369–1372.
Bausch D.G., Schwarz L. 2014. Outbreak of Ebola virus disease in Guinea: Where ecology meets economy. PLOS Neglected Trop. Dis. 8 (7), e3056.
Onishchenko G.G., Sandakhchiev L.S., Netesov S.V., Martynyuk R.A. 2003. Bioterrorism: A national and global threat. Herald Ross. Acad. Sci. 73 (2), 127–135.
Ignatyev G.M. 1998. Immune response to Filovirus infections. Curr. Top.Microbiol. Immunol. 235, 205–217.
Kuhn J.H., Andersen K.G., Bào Y., Bavari S., Becker S., Bennett R.S., Bergman N.H., Blinkova O., Bradfute S., Brister J.R., Bukreyev A., Chandran K., Chepurnov A.A., Davey R.A., Dietzgen R.G., Doggett N.A., Dolnik O., Dye J.M., Enterlein S., Fenimore P.W., Formenty P., Freiberg A.N., Garry R.F., Garza N.L., Gire S.K., Gonzalez J.P., Griffiths A., Happi C.T., Hensley L.E., Herbert A.S., Hevey M.C., Hoenen T., Honko A.N., Ignatyev G.M., Jahrling P.B., Johnson J.C., Johnson K.M., Kindrachuk J., Klenk H.D., Kobinger G., Kochel T.J., Lackemeyer M.G., Lackner D.F., Leroy E.M., Lever M.S., Mühlberger E., Netesov S.V., Olinger G.G., Omilabu S.A., Palacios G., Panchal R.G., Park D.J., Patterson J.L., Paweska J.T., Peters C.J., Pettitt J., Pitt L., Radoshitzky S.R., Ryabchikova E.I., Saphire E.O., Sabeti P.C., Sealfon R., Shestopalov A.M., Smither S.J., Sullivan N.J., Swanepoel R., Takada A., Towner J.S., van der Groen G., Volchkov V.E., Volchkova V.A., Wahl-Jensen V., Warren T.K., Warfield K.L., Weidmann M., Nichol S.T. 2014. Filovirus RefSeq entries: Evaluation and selection of Filovirus type variants, type sequences, and names. Viruses. 6, 3663–3682.
Olival K.J., Islam A., Yu M., Anthony S.J., Epstein J.H., Khan S.A., Khan S.U., Crameri G., Wang L.F., Lipkin W.I., Luby S.P., Daszak P. 2013. Ebola virus antibodies in fruit bats, Bangladesh. Emerg. Infect. Dis. 19, 270–273.
Taylor D.J., Leach R.W., Bruenn J. 2010. Filovirus are ancient and integrated into mammalian genomes. BMC Evol. Biol. 10, 193.
Lamb D., Schuttelkopf A.W., van Aalten D.M.F., Brighty D.W. 2011. Charge-surrounded pockets and electrostatic interactions with small ions modulate the activity of retroviral fusion proteins. PLOS Pathol. 7 (2), e1001268.
Blinov V.M. 1999. “Dormant” immunosuppressive domains (ISD) in filoviruses: activation of “Dormant” filoviruses by endogenous retroviruses. http://www.vector. nsc.ru/conf0999/posters/blinov/blinov.htm
Kiselev O.I. 2012. Immunosuppression during pregnancy and influenza. Vopr. Virusol. 57, 5–8.
Malashkevich V.N., Schnieder B.J., Mc Nally M.L., Milhollen M.A., Pang J.X., Kim P.S. 1999. Core structure of the envelope glycoprotein GP2 from Ebola virus at 1.9 Å resolution. Proc. Natl. Acad. Sci. U. S. A. 96, 2662–2667.
Subbotina E.L., Kachko A.V., Chepurnov A.A. 2006. Properties of Ebola virus proteins. Vopr. Virusol. 51 (6), 4–10.
WHO. 2014. Ebola response roadmap: Situation report (25 October 2014). http://apps.who.int/iris/bitstream/ 10665/137185/1/roadmapupdate25Oct14_eng.pdf
CDC. 2014. Ebola outbreak in West Africa. http://www. cdc.gov/vhf/ebola/outbreaks/2014-west-africa/
Chertow D.S., Kleine C., Edwards J.K., Scaini R., Giuliani R., Sprecher A. 2014. Ebola virus disease in West Africa: Clinical manifestations and management. N. Engl. J. Med. 371, 2054–2057.
Feldmann H., Sanchez A., Geisbert T.W. 2013. Filoviridae: Marburg and Ebola viruses. in Fields Virology, 6th ed. Eds. Knipe D.M., Howley P.M. Philadelphia: Lippincott, Williams & Wilkins, pp. 923–956.
Muhlberger E. 2007. Filovirus replication and transcription. Future Virol. 2 (2), 205–215.
Volchkov V.E., Becker S., Volchkova V.A., Ternovoj V.A., Kotov A.N., Netesov S.V., Klenk H.D. 1995. GP mRNA of Ebola virus is edited by the Ebola virus polymerase and by T7 and vaccinia virus polymerases. Virology. 214, 421–430.
Kondratowicz A.S., Lennemann N.J., Sinn P.L., Sinn P.L., Davey R.A., Hunt C.L., Moller-Tank S., Meyerholz D.K., Rennert P., Mullins R.F., Brindley M., Sandersfeld L.M., Quinn K., Weller M., Mc Cray P.B.,Jr., Chiorini J., Maury W. 2011. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zair Ebolavirus and Lake Victoria Marburgvirus. Proc. Natl. Acad. Sci. U. S. A. 108, 8426–8431.
Hunt C.L., Lenneman N.J., Maury W. 2012. Filovirus entry: A novelty in the viral fusion world. Viruses. 4 (2), 258–275.
Ramanan P., Shabman R.S., Brown C.S., Amarasinghe G.K., Basler C.F., Leung D.W. 2011. Filoviral immune evasion mechanisms. Viruses. 3 (9), 1634–1649.
Basler C.F., Wang X., Mühlberger E., Volchkov V., Paragas J., Klenk H.D., García- Sastre A., Palese P. 2000. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc. Natl. Acad. Sci. U. S. A. 97 (22), 12289–12294.
Mohan G.S., Li W., Ye L., Compans R.W., Yang C. 2012. Antigenic subversion: A novel mechanism of host immune evasion by Ebola virus. PLOS Pathog. 8 (12), e1003065.
Kreuels B., Wichmann D., Emmerich P., Schmidt Chanasit J., de Heer G., Kluge S., Sow A., Renné T., Günther S., Lohse A.W., Addo M.M., Schmiedel S. 2014. A case of severe Ebola virus infection complicated by Gram-negative septicemia. N. Engl. J. Med. 371 (16), 1481–1495.
Sanchez A., Lukwiya M., Bausch D., Mahanty S., Sanchez A.J., Wagoner K.D., Rollin P.E. 2004. Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: Cellular responses, virus load, and nitric oxide levels. J. Virol. 78 (19), 10370–10377.
World Health Organization. 2014. Consultation on potential Ebola therapies and vaccines: Background document for participants. http://www.who.int/csr/ disease/ebola/ebola-new-interventions-02-sep-2014.pdf? ua=1
Feldmann H., Geisbert T.W. 2011. Ebola haemorrhagic fever. Lancet. 377 (9768), 849–862.
Egorov A., Brandt S., Sereinig J., Romanova J., Ferko B., Katinger D., Grassauer A., Alexandrova G., Katinger H., Muster T. 1998. Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J. Virol. 72, 6437–6441.
Panchal R.G., Reid St.P., Tran J.P., Bergeron A.A., Wells J., Kota K.P., Aman J., Bavari S. 2012. Identification of an antioxidant small-molecule with broad-spectrum antiviral activity. Antiviral Res. 93 (1), 23–29.
Geisbert T.W., Young H.A., Jahrling P.B., Davis K.J., Kagan E., Hensley L.E. 2003. Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J. Infect. Dis. 188 (11), 1618–1629.
Ignat’ev G.M., Strel’tsova M.A., Agafonov A.P., et al. 1996. Experimental analysis of the possibility to treat MJarburg hemorrhagic fever with Desferal, Ribavirin, and homolohous interferon. Vopr. Virusol. 41, 206–209.
Geisbert T.W., Young H.A., Jahrling P.B., Davis K.J., Larsen T., Kagan E., Hensley L.E. 2003. Pathogenesis of Ebola hemorrhagic fever in primate models: Evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. Am. J. Pathol. 163 (6), 2371–2382.
Nakayama E., Masayuki S. 2013. Animal models for Ebola and Marburg virus infections. Front. Microbiol. 4, 267.
Groger M., Pasteiner W., Ignatyev G., Matt U., Knapp S., Atrasheuskaya A., Bukin E., Friedl P., Zinkl D., Hofer Warbinek R., Zacharowski K., Petzelbauer P., Reingruber S. 2009. Peptide Bß15-42 preserves endothelial barrier function in shock. PLOS ONE. 4 (4), e5391.
Ignat’ev G.M., Strel’tsova M.A., Kashentseva E.A., Patrushev N.A. 1998. Efficiency of tumor necrosis factor antiserum in treatment of Marburg hemorrhagic fever. Vestn. Ross. Akad. Nauk. 3, 35–38.
Feldmann H., Bugany H., Mahner F., Klenk H.D., Drenckhahn D., Schnittler H.J. 1996. Filovirusinduced endothelial leakage triggered by infected monocytes/macrophages. J. Virol. 70 (4), 2208–2214.
Wahl-Jensen V.M., Afanasieva T.A., Seebach J. 2005. Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function. J. Virol. 79 (16), 10442–10450.
Nakayama E., Takada A. 2011. Ebola and Marburg viruses. J. Disaster Res. 6 (4), 381–389.
Hensley L.E., Stevens E.L., Yan S.B., Geisbert J.B., Macias W.L., Larsen T., Daddario-Di Caprio K.M., Cassell G.H., Jahrling P.B., Geisbert T.W. 2007. Recombinant human activated protein C for the postexposure treatment of Ebola hemorrhagic fever. J. Infect. Dis. 15 (196), 390–399.
West T.E., von Saint André-von Arnim A. 2014. Clinical presentation and management of severe Ebola virus disease. Ann. Am. Thorac. Soc. 11 (9), 1341–1350. doi 10.1513/AnnalsATS.201410-481PS
Geisbert T.W., Hensley L.E., Jahrling P.B., Larsen T., Geisbert J.B., Paragas J., Young H.A., Fredeking T.M., Rote W.E., Vlasuk G.P. 2003. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: A study in rhesus monkeys. Lancet. 362 (9400), 1953–1958.
Nakayama E., Tomabechi D., Matsuno K., Kishida N., Yoshida R., Feldmann H., Takada A. 2011. Antibodydependent enhancement of Marburg virus infection. J. Infect. 204 (3), S978–S985.
Takada A., Feldmann H., Ksiazek T.G., Kawaoka Y. 2003a. Antibody-dependent enhancement of Ebola virus infection. J. Virol. 77, 7539–7544.
Takada A. 2012. Filovirus tropism: Cellular molecules for viral entry. Front. Microbiol. 3, 34.
Rekomendatsii po lecheniyu i profilaktike gemorragicheskoi likhoradki Ebola (Guidelines for Treatment and Prevention of Ebola Hemorrhagic Fever), 2014. St. Petersburg: NP-Print.
World Health Organization. 2014. Laboratory Guidance for the Diagnosis of Ebola Virus Disease: Interim Recommendations: September 2014. http://www.who.int/ iris/handle/10665/134009#sthash.5HKgzZSc.dpuf.
Wang Y., Zhang X., Wei H. 2011. Laboratory detection and diagnosis of filoviruses. Virol. Sinica. 26 (2), 73–80.
APA. 2014. Ebola: Experimentelles Medikament aus Wien in Frankfurt angewendet. https://science.apa. at/rubrik/medizin_und_biotech/Ebola_Experimentell es_Medikament_aus_Wien_in_Frankfurt_angewendet/ SCI_20141105_SCI39371351221083224
Li H., Ying T., Yu F., Lu L., Jiang S. 2014. Development of therapeutics for treatment of Ebola virus infection. Microbes Infect. 17 (2), 109–117. doi 10.1016/ j.micinf.2014.11.012
Geisbert T.W., Geisbert J.B., Leung A., Jiang S. 2009. Single-injection vaccine protects nonhuman primates against infection with Marburg virus and three species of Ebola virus. J. Virol. 83 (14), 7296–7304.
Falzarano D., Geisbert T.W., Feldmann H. 2011. Progress in filovirus vaccine development: Evaluating the potential for clinical use. Exp. Rev. Vaccines. 10 (1), 63–77.
Burki T.K. 2011. USA focuses on Ebola vaccine but research gaps remain. Lancet. 378, 389.
Geisbert T.W., Feldmann H. 2011. Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections. J. Infect. Dis. 204, S1075–S1081.
Terry M., Mc Dermid R. 2014. Ebola clinical trials: Big name players in the Ebola race. http://www.biospace. com/News/ebola-clinical-trials-big-name-players-in-the/ 350579#sthash.VBgE2Anv.SuOnEJhq.dpuf
Stanley DA, Honko A.N., Asiedu C., Trefry J.C., Lau Kilby A.W., Johnson J.C., Hensley L., Ammendola V., Abbate A., Grazioli F., Foulds K.E., Cheng C., Wang L., Donaldson M.M., Colloca S., Folgori A., Roederer M., Nabel G.J., Mascola J., Nicosia A., Cortese R., Koup R.A., Sullivan N.J. 2014. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nat. Med. 20 (10), 1126–1129. doi 10.1038/nm.3702
Olinger G.G. Jr., Pettitt J., Kim D., Working C., Bohorov O., Bratcher B., Hiatt E., Hume S.D., Johnson A.K., Morton J., Pauly M., Whaley K.J., Lear C.M., Biggins J.E., Scully C., Hensley L., Zeitlin L. 2012. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc. Natl. Acad. Sci. U. S. A. 109, 18030–18035.
CBC News. 2014. Ebola “cocktail” developed at Canadian and U.S. labs. http://www.cbc.ca/1.2727703
Enterlein S., Warfield K.L., Swenson D.L., Stein D.A., Smith J.L., Gamble C.S., Kroeker A.D., Iversen P.L., Bavari S., Mühlberger E. 2006. VP35 knockdown inhibits Ebola virus amplification and protects against lethal infection in mice. Antimicrob. Agents Chemother. 50 (3), 984–993.
Swenson D.L., Warfield K.L., Warren T.K., Lovejoy C., Hassinger J.N., Ruthel G., Blouch R.E., Moulton H.M., Weller D.D., Iversen P.L., Bavari S. 2009. Chemical modifications of antisense morpholino oligomers enhance their efficacy against Ebola virus infection. Antimicrob. Agents Chemother. 53 (5), 2089–2099.
Thi E.P., Mire C.E., Ursic-Bedoya R., Geisbert J.B., Lee A.C., Agans K.N., Robbins M., Deer D.J., Fenton K.A., Mac Lachlan I., Geisbert T.W. 2014. Marburg virus infection in nonhimans primates: Therapeutic treatment by lipid-encapsulated siRNA. Sci. Transl. Med. 6, 1–9.
Haussecker D. 2014. Developing aerosolized TKMEBOLA as airborne transmission of Ebola likely. http://rnaitherapeutics.blogspot.ru/2014/10/developingaerosolized-tkm-ebola-as.html
Wang Y., Liu Z., Dai Q. 2014. A highly immunogenic fragment derived from Zaire Ebola virus glycoprotein elicits effective neutralizing antibody. Virus Res. 189, 254–261.
Butler D. 2014. Ebola drug trials set to begin amid crisis. Testing drugs in the middle of deadly disease outbreak is challenging but can be done. Nature. 513, 13–14.
Côté M., Misasi J., Tao Ren T., Bruchez A., Lee K, Filone C.M., Hensley L., Li Q., Ory D., Chandran K., Cunningham J. 2011. Small molecule inhibitors reveal Niemann–Pick C1 is essential for Ebola virus infection. Nature. 477, 344–348.
Warren T.K., Wells J., Panchal R.G., Stuthman K.S., Garza N.L., Van Tongeren S.A., Dong L., Retterer C.J., Eaton B.P., Pegoraro G., Honnold S., Bantia S., Kotian P., Chen X., Taubenheim B.R., Welch L.S., Minning D.M., Babu Y.S., Sheridan W.P., Bavari S. 2014. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature. 508, 402–405.
Furuta Y., Gowen B.B., Takahashi K., Shiraki K., Smee D.F., Barnard D.L. 2013. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 100, 446–454.
Oesterreich L., Ludtke A., Wurr S., Rieger T., Muñoz Fontela C., Günther S. 2014. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res. 105, 17–21.
Smither S.J., Eastaugh L.S., Steward J.A., Nelson M., Lenk R.P., Lever M.S. 2014. Post-exposure efficacy of Oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antiviral Res. 104, 153–155.
Johansen L.M., Brannan J.M., Delos S.E. 2013. FDAapproved selective estrogen receptor modulators inhibit Ebola virus infection. Sci. Transl. Med. 5 (190), 190ra79.
de Wilde A.H., Jochmans D., Posthuma C.C., Zevenhoven-Dobbe J.C., van Nieuwkoop S., Bestebroer T.M., van den Hoogen B.G., Neyts J., Snijder E.J. 2014. Screening of an FDA-approved Compound Library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob. Agents Chemother. 58 (8), 4875.
Karpenko I., Deev S., Kiselev O.I., Charushin V., Rusinov V., Ulomsky E., Deeva E., Yanvarev D., Ivanov A., Smirnova O., Kochetkov S., Chupakhin O., Kukhanova M. 2010. Antiviral properties, metabolism, and pharmacokinetics of a novel azolo-1,2,4-triazinederived inhibitor of influenza A and B virus replication. Antimicrob. Agents Chemother. 54, 2017–2022.
Kiselev, O.I., Chupakhin, O.N., Rusinov, V.L., et al. 2012. RF Patent no. 2516936.
Hu Y., Xie G.H., Chen Q.X., Fang X.M. 2011. Small molecules in treatment of sepsis. Curr. Drug Targets. 12 (2), 256–262.
Blaising J., Lévy P.L., Polyak S.J., Stanifer M., Boulant S., Pécheur E.I. 2013. Arbidol inhibits viral entry by interfering with clathrin-dependent trafficking. Antiviral Res. 100 (1), 215–219.
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Original Russian Text © O.I. Kiselev, A.V. Vasin, M.P. Shevyryova, E.G. Deeva, K.V. Sivak, V.V. Egorov, V.B. Tsvetkov, A.Yu. Egorov, E.A. Romanovskaya-Romanko, L.A. Stepanova, A.B. Komissarov, L.M. Tsybalova, G.M. Ignatjev, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 4, pp. 541–554.
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Kiselev, O.I., Vasin, A.V., Shevyryova, M.P. et al. Ebola hemorrhagic fever: Properties of the pathogen and development of vaccines and chemotherapeutic agents. Mol Biol 49, 480–493 (2015). https://doi.org/10.1134/S002689331504007X
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DOI: https://doi.org/10.1134/S002689331504007X