Elsevier

Journal of Clinical Virology

Volume 64, March 2015, Pages 111-119
Journal of Clinical Virology

Ebola and Marburg haemorrhagic fever

https://doi.org/10.1016/j.jcv.2015.01.014Get rights and content

Highlights

  • Filoviruses are among the most virulent pathogens for humans and great apes.

  • The public health burden of filoviruses is limited despite their high virulence.

  • Disease is associated with striking virus replication and immune dysregulation.

  • Licensing of therapeutic options may be achievable over the next 5–10 years.

Abstract

Ebolaviruses and Marburgviruses (family Filoviridae) are among the most virulent pathogens for humans and great apes causing severe haemorrhagic fever and death within a matter of days. This group of viruses is characterized by a linear, non-segmented, single-stranded RNA genome of negative polarity. The overall burden of filovirus infections is minimal and negligible compared to the devastation caused by malnutrition and other infectious diseases prevalent in Africa such as malaria, dengue or tuberculosis. In this paper, we review the knowledge gained on the eco/epidemiology, the pathogenesis and the disease control measures for Marburg and Ebola viruses developed over the last 15 years. The overall progress is promising given the little attention that these pathogen have achieved in the past; however, more is to come over the next decade given the more recent interest in these pathogens as potential public and animal health concerns. Licensing of therapeutic and prophylactic options may be achievable over the next 5–10 years.

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.

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