Ebola virus: unravelling pathogenesis to combat a deadly disease

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Ebola virus (EBOV) causes severe haemorrhagic fever leading to up to 90% lethality. Increasingly frequent outbreaks and the placement of EBOV in the category A list of potential biothreat agents have boosted interest in this virus. Furthermore, development of new technologies (e.g. reverse genetics systems) and extensive studies on Ebola haemorrhagic fever (EHF) in animal models have substantially expanded the knowledge on the pathogenic mechanisms that underlie this disease. Two major factors in EBOV pathogenesis are the impairment of the immune response and vascular dysfunction. Here, we attempt to summarize the current knowledge on EBOV pathogenesis focusing on these two factors and on recent progress in the development of vaccines and potential therapeutics.

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Molecular biology of Ebola virus

Ebola viruses (EBOV) belong to the Filoviridae family (order Mononegavirales). The genus Ebolavirus (EBOV) is subdivided into four species: Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SEBOV), Ivory Coast ebolavirus (ICEBOV) and Reston ebolavirus (REBOV) [1].

The 18.9-kb RNA genome of EBOV is non-infectious and encodes seven structural proteins and one non-structural protein in the following order within the genome: 3′ non-coding region (leader), nucleoprotein (NP), virion protein 35 (VP35),

Epidemiology

Since its identification in 1976, there have been 1849 reported cases of Ebola haemorrhagic fever (EHF) including 1288 deaths (Table 1); all the outbreaks occurred in the tropical African ecosystem and were located between latitudes 5° North and 5° South. The epidemiology of human Ebola virus infections in nature is unknown. However, the time between the occurrence of index cases and the recognition of subsequent large outbreaks, in addition to the possible occurrence of asymptomatic

Clinical presentation

EBOV infection in humans and NHPs results in a particularly virulent form of viral haemorrhagic fever. Following an incubation of 4–10 days [2], fever of >38.3°C abruptly develops. Additional early symptoms are non-specific and can include chills, muscle pain, nausea, vomiting, abdominal pain and/or diarrhoea 8, 9, 10. Swelling of the lymph nodes, kidneys or brain, as well as necrosis of the liver, lymph organs, kidneys, testis and ovaries can occur. All patients show some extent of impaired

Animal models

In recent years, there has been significant progress towards the understanding of the pathogenic mechanisms that underlie EHF. However, there are only limited data regarding the pathophysiology of EHF in humans owing to the occurrence of outbreaks in remote areas and the lack of facilities that enable safe and thorough investigations during an outbreak 16, 17. Therefore, the development of animal models for EHF has been invaluable in increasing the knowledge of EBOV pathogenesis. At present,

Treatment

At present, the treatment for EHF is mainly supportive and involves a combination of intravenous-fluid replacement, administration of analgesics and standard nursing measures [25].

Despite the lack of any specific antiviral drugs for the treatment of EHF, a few experimental approaches have shown promise in recent years. In particular, because overexpression of TF has such a profound effect in the development of DIC, the possibility of inhibiting this pathway has been considered as a therapeutic

Concluding remarks

EBOV is a highly pathogenic virus that has caused an increasing number of outbreaks in central Africa in the past decade. Because of its high fatality rate and potential use as a bioweapon, it is very important to understand its mechanisms of pathogenesis and, ultimately, to develop vaccines and therapeutics.

The current model for EBOV pathogenesis is that, after entering the host, EBOV targets macrophages and DCs, thereby inducing an inflammatory state with high levels of proinflammatory

Acknowledgements

The authors gratefully acknowledge H. Ebihara (Institute for Medical Science, University of Tokyo, Japan) and S. Becker (Philipps Universität Marburg, Germany) for their valuable discussion, and S. Bamberg and L. Kolesnikova (Philipps Universität Marburg, Germany) for providing source material for the figures. Work on filoviruses at the National Microbiology Laboratory is supported by the Public Health Agency of Canada, the Canadian Institutes of Health Research (MOP-43921) and the National

Glossary

Adaptive immunity:
components of the immune system that are acquired after birth. These are characterized by specific immune responses to an antigen, including antibody production by B cells, selection of active T cells, T-cell apoptosis and development of immunological memory.
Animal model:
refers to an animal species that is sufficiently similar to humans in its response to an injury or disease so that it can be used in medical research to obtain information that can be extrapolated for human

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