Ebola and Marburg haemorrhagic fever
Introduction
Filoviruses are part of the order Mononegavirales together with the Rhabdoviridae, the Paramyxoviridae and the Bornaviridae families. In this order, viruses are characterized by a lipid envelope and a non-segmented single-stranded RNA (ssRNA) genome of negative polarity [1], [2], [3]. Filovirus particles are long filaments shaped in several different forms such as the number ‘6’, the letter ‘U’ or a circle, which give them a rather unique morphology in the viral world (Fig. 1). Viruses of the Ebolavirus, Marburgvirus, and Cuevavirus genera are the only representatives of the Filoviridae family. The Ebolavirus and Marburgvirus genomes are about 19,000 nucleotides long and are transcribed into eight major subgenomic mRNAs. These mRNAs encode seven structural proteins, nucleoprotein (NP), virion protein 35 (VP35), VP40, glycoprotein (GP), VP30, VP24, and RNA-dependent RNA polymerase (L), as well as two nonstructural proteins, soluble (sGP) and small soluble glycoprotein (ssGP) (Fig. 1A–B). Nowadays, seven species of filoviruses have been identified and classified [4]. Specifically, the genus Ebolavirus is composed of five recognized species: Tai Forest ebolavirus (Tai Forest virus, TAFV), Reston ebolavirus (Reston virus, RESTV), Sudan ebolavirus (Sudan virus, SUDV), Zaire ebolavirus (Ebola virus, EBOV), and Bundibugyo virus (Bundibugyio virus, BDBV) (Table 1). The genus Marburgvirus consists of only one species, Marburg margburgvirus, which includes two viruses with approximately 20% genetic divergence: Marburg virus (MARV) and Ravn virus (RAVV). Finally, the genus Cuevavirus is composed of one species called Lloviu cuevavirus (Lloviu virus, LLOV) (Table 1).
Among the seven species of filoviruses, four (SUDV, EBOV, BDBV and MARV) are responsible for fatal outbreaks of haemorrhagic fever in Africa, for which there is no effective treatment. These viruses are also responsible for several outbreaks that contributed to ecological disasters in terms of population density decreases of chimpanzees and gorillas, especially in Gabon, Uganda, and the Republic of Congo. The case fatality in human populations due to EBOV is the highest, with about 90% [2], [5]. The other species have lower case fatality rates, with 42–65% for SUDV [6] and between 34% and 44% for BDBV [7], [8], [9]. Marburgvirus infections lead to death in about 24–88% of cases depending on the outbreak [10], [11]. Only one other species, for which unknown virulence has been observed, has been reported in Africa, the TAFV. Indeed, this TAFV has only been responsible of one non-fatal human case [12]. The two other species not responsible for outbreaks in human populations have been identified in Asia and Europe. RESTV, originating from the Philippines, has been responsible for infections and death in nonhuman primates. Finally, more recently LLOV, an Ebola-like filovirus, has been identified in insectivorous bats in Spain [13]. In contrast to MARV and EBOV that have been reported to asymptomically circulate in bats (evolution through avirulence), several observations suggested that LLOV might be pathogenic for bats [13].
Over the past 45 years, the global public health burden of filoviruses has been limited despite their high virulence and impact on African ecosystems. The extreme virulence and the communicable nature of these viruses together with the lack of countermeasures made them biothreat pathogens in the post-Cold war era [14], [15], [16]. Since 15 years, research in biology, ecology, evolution, epidemiology and pathophysiology has remarkably advanced leading to a better understanding of virus biology and development of therapeutic/antiviral strategies and candidate vaccines [17], [18], [19], [20], [21], [22]. In this paper, we review achievements in the eco-epidemiology (outbreak history and description), pathogenesis, diagnostic, prophylaxis, and therapy.
Section snippets
Advances in eco-epidemiology, outbreaks history
Marburgviruses and ebolaviruses have caused only a few documented outbreaks since their discovery 45 years ago. Until 2014, outbreaks have been responsible for 2989 clinical cases of which 2068 have died (Table 1, Table 2, and Fig. 2). The overall burden of filoviruses is low in comparison to others diseases such as malaria or malnutrition.
Marburgviruses outbreaks
The first outbreak of filoviral haemorrhagic fever happened in 1967 simultaneous in Germany (Marburg and Frankfurt) and Yugoslavia (Belgrade). A total of 32
Advances in basic virology, mechanisms of pathogenesis
Even if the scientific advances considerably increased our knowledge of filovirus, we are still far from understanding clearly the pathogenesis and immune responses of infections with these pathogens. The four pathogenic filovirus species are known to cause the most severe haemorrhagic fever syndromes in human and non-human primates, with case fatality rates in humans of up to 90% [8], [11], [25], [26], [30], [32], [43], [44] (Table 2). Following an incubation period of 2 to 21 days (mean of
Advances in clinical virology: advances in diagnostics and bedside tests
Since rapid confirmation of a filovirus infection through laboratory diagnosis is fundamental, fast, sensitive and specific tests have been developed. Moreover, confirmatory tests are recommended to avoid any misdiagnosis and any potential critical social consequences of it. Blood and tissue samples suspected for filoviruses infections must be handled in biosafety level 4 laboratory.
Laboratory diagnosis is separated into direct and indirect detection assays. Among the direct detection assays,
Advances in prophylaxis and therapy: vaccine and antivirals
Currently no specific therapy exists for filovirus infections [90], [91]. Supportive care is adopted consisting of rehydration, nutritional supplementation and psychosocial support [92]. Intravenous fluid replacement to maintain blood volume, blood pressure and electrolyte balance, as well as analgesics and standard barrier nursing are critical. In the past, convalescent serums, extracorporal blood treatment with haemosorbent and dialysis, and IFN were used to treat human filovirus cases, but
Funding
We thank the Gabonese Government, Total Gabon, the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 593 and 1021 (Germany) and the Intramural Research Program of NIAID, NIH (U.S.A) for financial support.
Competing interests
N/A.
Ethical approval
N/A.
Acknowledgement
N/A.
References (121)
- et al.
Marburg and Ebola viruses
Adv. Virus Res.
(1996) - et al.
Ebola haemorrhagic fever
Lancet
(2011) - et al.
Ebola virus: unravelling pathogenesis to combat a deadly disease
Trends Mol. Med.
(2006) - et al.
Isolation and partial characterisation of a new strain of Ebola virus
Lancet
(1995) - et al.
Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection
Am. J. Pathol.
(2003) Marburg agent disease: in man
Trans. R. Soc. Trop. Med. Hyg.
(1969)- et al.
Identification of the Ebola virus in Gabon in 1994
Lancet
(1997) - et al.
Containing a haemorrhagic fever epidemic: the Ebola experience in Uganda (October 2000–January 2001)
Int. J. Infect. Dis.
(2004) - et al.
Marburg-virus disease in Kenya
Lancet
(1982) - et al.
Protection from lethal infection is determined by innate immune responses in a mouse model of Ebola virus infection
Virology
(2003)
Association of Ebola-related Reston virus particles and antigen with tissue lesions of monkeys imported to the United States
J. Comp. Pathol.
Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily
Immunol. Lett.
Evidence against Ebola virus sGP binding to human neutrophils by a specific receptor
Virology
Re-emergence of ebola haemorrhagic fever in Gabon
Lancet
Modifications to indirect immunofluorescence tests on Lassa, Marburg, and Ebola material
Lancet
3-deazaneplanocin A induces massively increased interferon-alpha production in Ebola virus-infected mice
Antiviral Res.
The international code of virus classification and nomenclature (ICVCN): proposal to delete Rule 3.41
Arch. Virol.
Ebola virus disease in southern Sudan: hospital dissemination and intrafamilial spread
Bull. World Health Org.
Proportion of deaths and clinical features in Bundibugyo Ebola virus infection, Uganda
Emerg. Infect. Dis.
Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda
PLoS Pathog.
Ebola hemorrhagic fever associated with novel virus strain, Uganda, 2007–2008
Emerg. Infect. Dis.
Risk factors for Marburg hemorrhagic fever, Democratic Republic of the Congo
Emerg. Infect. Dis.
Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola
J. Virol.
Discovery of an ebolavirus-like filovirus in europe
PLoS Pathog.
Filovirus research: knowledge expands to meet a growing threat
J. Infect. Dis.
Filoviruses–a compendium of 40 years of epidemiological, clinical, and laboratory studies
Arch. Virol. Suppl.
Public health assessment of potential biological terrorism agents
Emerg. Infect. Dis.
Ebola virus: from discovery to vaccine
Nat. Rev. Immunol.
Ebola and Marburg viruses: pathogenesis and development of countermeasures
Curr. Mol. Med.
Filovirus-like particles as vaccines and discovery tools
Expert Rev. Vacc.
Development of treatment strategies to combat Ebola and Marburg viruses
Expert Rev. Anti. Infect. Ther.
Outbreaks of filovirus hemorrhagic fever: time to refocus on the patient
J. Infect. Dis.
[On an infectious disease transmitted by Cercopithecus aethiops: (Green monkey disease)]
Dtsch Med Wochenschr
Fatal human disease from vervet monkeys
Lancet
Marburg hemorrhagic fever associated with multiple genetic lineages of virus
N. Engl. J. Med.
The epidemic of Ebola haemorrhagic fever in Sudan and Zaire, 1976: introductory note]
Ebola haemorrhagic fever in Zaire, 1976
Ebola haemorrhagic fever in Sudan, 1976. Report of a WHO/International Study Team
Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients
J. Infect. Dis.
The reemergence of Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995. Commission de Lutte contre les Epidëmies à Kikwit
J. Infect. Dis.
Ebola hemorrhagic fever outbreaks in Gabon, 1994–1997: epidemiologic and health control issues
J. Infect. Dis.
Isolation and phylogenetic characterization of Ebola viruses causing different outbreaks in Gabon
Emerg. Infect. Dis.
An outbreak of Ebola in Uganda
Trop. Med. Int. Health
Reemerging Sudan Ebola virus disease in Uganda, 2011
Emerg. Infect. Dis.
Cited by (108)
Ebola virus VP35 perturbs type I interferon signaling to facilitate viral replication
2023, Virologica SinicaGenome structure and genetic diversity in the Ebola virus
2021, Current Opinion in PharmacologyMarburg virus disease: A summary for clinicians
2020, International Journal of Infectious DiseasesCitation Excerpt :Significant viral replication occurs in target organs such as the spleen, liver and secondary lymphoid organs. The virulence and high morbidity/mortality of the disease appears related to unchecked viral replication (related in part to inhibition of IFN-1 synthesis), as people with ultimately fatal infections generally exhibit high viral loads (Rougeron et al., 2015). This replication is facilitated by the virus's ability to undercut the host immune response by exploiting intracellular and extracellular immune-mediated antiviral pathways (Cross et al., 2018).
Distinct Genome Replication and Transcription Strategies within the Growing Filovirus Family
2019, Journal of Molecular BiologyCurrent status of small molecule drug development for Ebola virus and other filoviruses
2019, Current Opinion in Virology