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Ebola Hemorrhagic Fever: Properties of the Pathogen and Development of Vaccines and Chemotherapeutic Agents O

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Ebola Hemorrhagic Fever: Properties of the Pathogen and Development of Vaccines and Chemotherapeutic Agents O ISSN 00268933, Molecular Biology, 2015, Vol. 49, No. 4, pp. 480–493. © Pleiades Publishing, Inc., 2015. 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. RomanovskayaRomanko, 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. REVIEWS UDC 578.2,578.76 Ebola Hemorrhagic Fever: Properties of the Pathogen and Development of Vaccines and Chemotherapeutic Agents O. I. Kiseleva, A. V. Vasina, b, M. P. Shevyryovac, E. G. Deevaa, K. V. Sivaka, V. V. Egorova, V. B. Tsvetkova, d, A. Yu. Egorova, E. A. RomanovskayaRomankoa, L. A. Stepanovaa, A. B. Komissarova, L. M. Tsybalovaa, and G. M. Ignatjeva a Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, 197376 Russia; email: [email protected] b St. Petersburg State Polytechnic University, St. Petersburg, 195251 Russia c Ministry of Health of the Russian Federation, Moscow, 127994 Russia d Topchiev Institute of Petrochemical Synthesis, Moscow, 119991 Russia Received December 29, 2014; in final form, January 16, 2015 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 distinc tions 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 find ings in therapy of severe conditions leading to a fatal outcome. DOI: 10.1134/S002689331504007X Keywords: Ebola virus, hemorrhagic fever, genome, interferon antagonists, vaccines, antiviral drugs It’s a pity that so much research requiring military units to bring the affected territories has the biological weapon aspect under control. Yet the most important lessons learned in mind rather than helping from the current situation with EHF are that health the affected population. care systems are not prepared for such outbreaks in Esther Sterk, Médecins Sans Frontières virtually all countries, vaccines are difficult to develop, and highly effective broadspectrum antiviral chemo therapy agents are unavailable. INTRODUCTION The first recorded outbreak of Ebola hemorrhagic EBOLA HEMORRHAGIC FEVER VIRUS fever (EHF) occurred in October 1976 in the Demo AND OUTBREAK OF 2013–2014 cratic Republic of Congo [1]. The outbreak of 2013– The virus Zaire ebolavirus is a causal agent of the 2014 is thought to share many features with the out EHF outbreak in West Africa. The Ebola virus was first break of 1976 [2], both being caused by the Zaire identified in 1976 and caused sporadic EHF outbreaks Ebola virus and starting in rural forested areas where with a high mortality in Africa, being assigned conse hunting for bush meat is common [1]. Patients were quently to group A pathogens, which are potential bio admitted to regional hospitals in grave conditions with terrorism agents [1, 4]. In terms of general virology, symptoms resembling malaria, typhoid fever, Lassa the Ebola virus is currently a reference standard of fever, yellow fever, or influenza [2, 3] The epidemics pathogenicity, and its studies are of basic importance was a severe challenge for the health care systems of for solving the most complex problems in treating and West African countries, and the total illpreparedness preventing virus infections. of the community caused panic and social upheaval, The species Zaire ebolavirus is the most pathogenic Abbreviations: EHF, Ebola hemorrhagic fever; DIC, dissemi species of the genus Ebolavirus (family Filoviridae, nated intravascular coagulation. order Mononegavirales). The family Filoviridae 480 EBOLA HEMORRHAGIC FEVER 481 Order Mononegavirales Family Filoviridae Genus Ebolavirus Species Taï Forest ebolavirus Virus: Tai Forest virus (TAFV) Species Reston ebolavirus Virus: Reston virus (RESTV) Species Sudan ebolavirus Virus: Sudan virus (SUDV) Species Zaire ebolavirus Virus: Ebola virus (EBOV) Species Bundibugyo ebolavirus Virus: Bundibugyo virus (BDBV) Fig. 1. Classification of viruses of the genus Ebolavirus. The virus responsible for the EHF outbreak of 2014 in West Africa is in bold [1, 2, 6]. includes three genera: Ebolavirus, Marburgvirus, and EPIDEMIOLOGY OF EBOLA Cuevavirus. Ebolavirus species are morphologically HEMORRHAGIC FEVER similar to Marburgvirus species, but have different A team of WHO epidemiologists identified the antigens. The genus Ebolavirus includes five species: Ebola virus as a causal agent of the hemorrhagic fever Sudan ebolavirus, Zaire ebolavirus, Taï Forest ebolavi outbreak that occurred in the Ebola River valley rus, Reston ebolavirus, and Bundibugyo ebolavirus. (Zaire, Central Africa) in 1976 [1–3]. A total of Infection with Reston ebolavirus is asymptomatic, 23 EHF outbreaks were registered since that time. The while the other four species are highly pathogenic for outbreak of 2014 started in Guinea (West Africa) and humans [1–5]. The taxonomy of the genus Ebolavirus spread to Liberia, Sierra Leone, and Nigeria. A phylo has been considered in a special article published in genetic analysis of Ebola virus genomic sequences Viruses [6] by a team including Russian researchers gives grounds to think that the virus strain responsible who contributed substantially to studying the problem for the 2014 outbreak relatively recently found its way both in Russia and abroad. A current classification of from Central to West Africa [2, 3]. the genus Ebolavirus is shown in Fig. 1. A phylogenetic analysis confirmed genetic similar The Ebola virus is found in primates, field mice, ity between Ebola virus lineages involved in the three and bats. In bats, infection does not lead to a disease last EHF outbreaks. The finding suggests a common outbreak and is virtually asymptomatic. The fact sug ancestor for the viruses involved and supports the gests that bats, in particular, fruit bats of the family hypothesis that each EHF outbreak was caused by Pteropodidae, are a natural reservoir and intermediate independent transmission of the virus from one genet host of the Ebola virus [7]. A genetic analysis of Ebola ically diverse population [2]. The genetic similarity virus isolates showed that the current outbreak started and close phylogenetic relationship of the genomes of with virus transmission from the strawcolored fruit 2014 Ebola viruses indicate that a single act of trans bat Eidolon helvum to humans [2]. It should be noted mission from a natural reservoir was followed by stable that a greater range of intermediate hosts is possible for transmission of infection among humans, leading to the virus. an epidemic outbreak. This epidemiological situation basically differs, for instance, from epidemics of avian It is of interest that viruses of the family Filoviridae flu, which was characterized by multiple focal out belong to a limited group of viruses, known as the non breaks in endemic regions and a low transmission rate retroviral integrated RNA viruses (NIRVs), whose among humans. Hence, Ebola virus infection seems to specific elements were identified in animal genomes be extremely contagious. There are estimates that a [8]. A high structural similarity was observed for the single event of crossing the species barrier would be receptor protein GP of the Ebola virus with the Env enough for the virus to spread rapidly in the popula proteins of endogenous retroviruses and placental syn tion [2]. cytins of humans [9]. Common elements of the Ebola The EHF outbreak starting in December 2013 virus and retrovirus are of principal importance for involved mostly Guinea, Liberia, Senegal, Sierra understanding the key factors of the Ebola virus Leone, and Nigeria among African countries [14–16]. pathogenicity [10, 11]. A high similarity was addition Cases observed in the United States and European ally detected between Ebola virus GP and wellknown countries occurred in healthcare workers and mission influenza virus hemagglutinin, facilitating a better aries. Estimates published in mass media for the risk of understanding of the GP tertiary structure and inhibi EHF being transferred to other countries, including tor design [12, 13]. Russia, are based on the passenger traffic statistics and MOLECULAR BIOLOGY Vol. 49 No. 4 2015 482 KISELEV et al. (a) EBOLA OUTBREAK RESPONSE: REGIONAL CONFIRMED AND PROBABLE CASES MAP DATE: 29 October 2014 Recent Cases (21 Days Prior) All cases 1–10 1–10 11–100 11–100 101–200 101–200 201–400 201–500 401–800 501–1000 NOT ACTIVENo cases in previous 21 days ACTIVENew cases in previous 21 days NEWLY INFECTEDNew cases in previous 7 days (in previously uninfected areas) (b) 1.2 Total cases, million people (Liberia and Sierra Leone 1.0 Without medical care With medical care (70% of cases are 0.8 localized in treatment centers 0.6 0.4 0.2 0 24 24 23 22 22 21 21 20 June July Aug Sep Oct Nov Dec Jan Source: Centers for Disease Control (CDC) Patterson Clark, The Washington Post Fig. 2. EHF geographic distribution and morbidity in West African regions. (a) Distribution of EHF in West Africa with the num ber of cases shown graphically (WHO data as of October 25, 2014).
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