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Ebola Viruses

  1. Anthony Sanchez

Published Online: 22 JUL 2003

DOI: 10.1038/npg.els.0001019

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How to Cite

Sanchez, A. 2003. Ebola Viruses. eLS. .

Author Information

  1. Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Publication History

  1. Published Online: 22 JUL 2003

Molecular Biology

  1. Top of page
  2. Molecular Biology
  3. Pathology and Pathogenesis
  4. Epidemiology
  5. Patient Management and Control
  6. References
  7. Further Reading

Ebola viruses have evolved to occupy some unknown niche. The ability of these filoviruses to exist in the wild and cause disease in human and nonhuman primates derives from the peculiarities and dynamics of the molecules that are produced by these pathogens. Ebola viruses evolved from a progenitor virus, which also gave rise to a multitude of other human pathogens, such as Measles virus and Rabies virus. The manner in which these viruses replicate their genomes and express proteins from their genes is greatly influenced by the types of host cells they are capable of infecting. The characteristic effects of their molecular interactions within the host dictates the type, severity and duration of infection. An important aspect in the pathogenesis of Ebola viruses is their ability to affect the immune responses of human and/or nonhuman primates and the wide range of tissues that support the growth of these viruses. See also Filoviruses, Measles Virus, and Rabies Virus

Genome organization

The single-stranded ribonucleic acid (RNA) genome of the Zaire species of Ebola virus is nearly 19 000 bases in length and is very similar in organization to that of Marburg virus. The genome organization and gene structure is consistent with those of paramyxoviruses and rhabdoviruses. Figure 1 illustrates the genome with seven linearly arranged genes (Sanchez et al., 1993). At the extreme 3′- and 5′-ends are short, extragenic regions (known as leader and trailer sequences) that are important in the initiation and regulation of viral RNA synthesis. Genes are delineated by conserved transcriptional signals for synthesis of positive-sense messenger RNA (mRNA) (a start site at the 3′-end and a stop or polyadenylation site at the 5′-end), and adjacent genes are either separated by a short intergenic region (also extragenic) or share short sequences that are limited to transcriptional signals (overlap). Intergenic regions and overlaps alternate along the genome of the Zaire species. The Reston species differs from Zaire species in that the overlap between the glycoprotein and VP30 genes is absent and an intergenic region separates them. The sequence 3′-UUAAU is common to both start and stop signals and is positioned in the centre of overlaps. As seen in Figure 1, there is a large amount of noncoding sequence in the genome and its function in expression is unclear. Stem–loop structures are also predicted for the sequences at the beginnings of the genes and also the extreme 3′- and 5′-ends of the genome (also seen in Marburg virus). These structures are present in mRNA and may improve their translation; comparable structures have not been identified in viruses from other families in the order Mononegavirales. See also Marburg virus, Rhabdoviruses, and RNA Virus Genomes

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Figure 1. Ebola virus (Zaire species) genomic RNA. Coding regions for seven linearly arranged genes are shown as hatched boxes. The scale at the bottom of the figure indicates units of sequence length numbered in kilobases. IR, intergenic region.

Expression of the glycoprotein gene and structures of SGP and GP

As with many other viruses, products of the glycoprotein gene of Ebola viruses play an important role in virus entry and pathogenesis. The organization of the glycoprotein genes of all Ebola viruses is unusual and differs from similar genes of other viruses, including Marburg virus in the same Filoviridae family. Figure 2 depicts the organization and expression strategy of an Ebola virus glycoprotein gene. This gene encodes two prominent proteins, a secreted glycoprotein (SGP) that is released from infected cells in large amounts as a homodimer, and a structural glycoprotein (GP) that forms trimers of a membrane-anchored heterodimer; GP trimers form the peplomers or ‘spikes’ on the surface of virions. The nonstructural SGP is expressed in preference to the structural GP, with mRNA for GP produced through a transcriptional editing mechanism (Sanchez et al., 1996). The editing event that leads to GP expression is an insertion of a single extra adenosine at a run of seven adenosines in the middle of the coding region. This insertion connects the 0 and −1 frames that encode the full-length GP and occurs in about 25% of the transcripts. The coding frame shared by SGP and GP and the frame accessed by editing are seen in Figure 2. As a consequence of this organization, SGP and GP share the same N-terminal ∼300 amino acids with unique C-termini, both in length and sequence. See also , and Glycoproteins

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Figure 2. Organization and expression of the glycoprotein genes of Ebola viruses, showing the production of the secreted SGP homodimer as the primary gene product from an unedited transcript, and the structural GP trimer through a transcriptional editing event (single adenosine insertion).

Roles of SGP and GP molecules

The role of the SGP molecule is unclear, but it is known that SGP dimers are structurally very distinct from multimers of GP (Sanchez et al., 1998). The SGP dimer also has a different cell binding pattern, so it appears that their roles are separate (Yang et al., 1998). It is likely that expression of significant quantities of SGP is important in the natural host and could function in establishing a persistent infection through interactions with certain white blood cells, or possibly binding soluble mediators produced in response to infections. In acute human cases, SGP is circulating in the blood in fairly large amounts and may contribute to the pathogenesis of Ebola virus infections of human and nonhuman primates. Efforts are under way to examine the interaction of SGP with cells and molecules in the human body, and also to determine the three-dimensional structure of SGP to better understand the actions of this molecule.

The GP molecule has an important role in initiating infections, as the large peplomers covering the surface of virions function in the recognition of and attachment to specific but currently unknown cell receptors (Wool-Lewis and Bates, 1998). The spike structures of Ebola virus have been shown to bind to endothelial cells and not to lymphocytes, which are not infected by Ebola virus. It is also believed to cause fusion of virion and cell membranes, which results in the release of the nucleocapsid into the cytoplasm. Structural studies have shown that GP is cleaved at a single site in the N-terminal third of the molecule by furin, a cellular subtilisin/kexin-like convertase, into GP1 (N-terminal end) and GP2 that are joined by a disulfide bond (Volchkov et al., 1998). GP1 is highly glycosylated and contains most of the N- and O-linked glycans present in the surface spike. GP1 projects away from the surface of the virion and probably functions in receptor binding. The glycosylation of GP1 affects the folding of the molecule and may also be important in immune evasion. Virions of Ebola viruses (and filoviruses in general) are resistant to neutralization by antibody specific for the surface glycoprotein, and this may be due to the large amount of nonimmunogenic carbohydrate covering GP1, accounting for 60% or more of the molecular weight (GP1 = 130 kDa). GP2 contains an α-helical sequence important in trimerization through the formation of coiled coils. The GP2 trimer forms a membrane-anchored, rod-like stalk that stabilizes the peplomer and contains a sequence positioned near its N-terminus that has been shown in vitro to promote fusion of membranes (fusion peptide) dependent on the presence of phosphatidylinositol and calcium (Weissenhorn et al., 1998). It would thus appear that the role of GP2 lies in the formation and stabilization of the virion spike and fusion of the virus and host cell membranes during infection. The structural picture that is being revealed for the Ebola virus GP (as well as that of Marburg virus) is very similar to the glycoproteins of retroviruses and influenza viruses. See also Virus Host Cell Receptors, Virus Replication, and Influenza Viruses: Molecular Virology

Pathology and Pathogenesis

  1. Top of page
  2. Molecular Biology
  3. Pathology and Pathogenesis
  4. Epidemiology
  5. Patient Management and Control
  6. References
  7. Further Reading

Histology

In severe and fatal cases of Ebola virus infection, as with infections with other haemorrhagic fever viruses, there is an extensive multiorgan involvement, with focal to widespread necrosis. There is no inflammation (i.e. infiltration of neutrophils and other phagocytic cells) in tissues infected with Ebola virus, which has been suggested to be the result of an immunosuppression induced by the virus. Immunohistochemical staining of the liver reveals massive amounts of virus antigen in hepatocytes, Kupffer cells, and endothelial cells, and antigen is also deposited in the intercellular connective tissues; the reticuloendothelial cell system is heavily involved. The spleen is another target organ for the replication of Ebola virus, and in addition to large amounts of antigen, there is follicular necrosis and a general loss of structural organization. Examination of tissues from infected humans, monkeys and guinea pigs has shown that cells of the mononuclear phagocytic system (macrophages and monocytes) are infected by Ebola virus. It is possible that infection and replication in these cell types early in the course of the disease may contribute to some form of immunosuppression, especially if these and other cells are induced to secrete substances that disrupt signalling or are rendered ineffective in clearing the virus from the body. See also Immune Response: Evasion and Subversion by Pathogens

Disruption of immune responses

It is known that an immunosuppression is established early in the course of infections of human and nonhuman primates, and development of a strong cellular immune response is critical to surviving Ebola virus infections. There is some indication that inactivated virions of Ebola virus are capable of inhibiting the proliferation of T lymphocytes, which would contribute to immunosuppression. Humoral (antibody) responses do not appear to be as important to virus clearance, as virions of filoviruses are difficult to neutralize (even when treated with high-titre anti-GP sera), and antibody levels are usually very low or undetectable at the critical time when cell-mediated clearance of the virus either begins or fails to develop. See also T Lymphocytes: Cytotoxic, T Lymphocytes: Helpers, and Immunity: Humoral and Cellular

Based on results from histological and in vitro studies, Ebola viruses are capable of infecting endothelial cells. Infection of primary cell cultures of human umbilical vein endothelial cells with the Zaire species of Ebola virus results in a disruption of the signalling processes in these cells without a shutdown of host cell protein synthesis. This disruption suppresses the induction of immunomodulatory genes (e.g., major histocompatibility complex (MHC) class I and class II, interleukin 6 (IL-6), intracellular adhesion molecule 1 (ICAM-1) etc.) that are important in helping to clear the body of infections. The mechanism of this suppression has not been characterized, so disruption of cellular functions by Ebola virus may occur at the cell membrane, within the cytoplasm, at the nuclear membrane, or at any combination of these sites. See also Innate Immune Mechanisms: Nonself Recognition, and Major Histocompatibility Complex (MHC)

Epidemiology

  1. Top of page
  2. Molecular Biology
  3. Pathology and Pathogenesis
  4. Epidemiology
  5. Patient Management and Control
  6. References
  7. Further Reading

Outbreaks of Ebola viruses that cause severe disease in humans have originated in rural areas (tropical forests or savannah) of what was formerly Zaire (now the Democratic Republic of the Congo), Sudan and Côte d'Ivoire (Table 1). The original 1976 outbreaks in northern Zaire and southern Sudan involved two different species of Ebola virus that emerged simultaneously. The events or conditions that triggered these concurrent outbreaks are unexplained, and subsequent reemergences have failed to shed any light on the factors involved in precipitating Ebola outbreaks. The Reston species of Ebola virus, which has not been shown to be pathogenic for humans, has been isolated from monkeys (Macaca fascicularis) native to the Philippines. However, the Reston species has not been detected in monkeys directly from the wild and has only been associated with a single Philippine breeding/exporting facility that has been the source of all outbreaks caused by the Reston species. The possibility that this virus was introduced into the facility through trafficking of nonhuman primates (from Africa?) cannot be dismissed.

Table 1. Outbreaks of Ebola virus infections of humans and/or nonhuman primates
Ebola virus speciesaYearLocations of outbreaksHuman cases (% mortality)
  1. a

    Outbreak confirmed by virus isolation.

Zaire1976Yambuku, Zaire318 (88)
Sudan1976Nzara and Maridi, Sudan284 (53)
Zaire1977Tandala, Zaire1 (100)
Sudan1979Nzara and Yambio, Sudan34 (65)
Reston1989Reston, Virginia, USA4 (0)
  Calamba, Philippines 
Reston1992Siena, Italy0
  Calamba, Philippines 
Côte d'Ivoire1994Tai Forest, Côte d'Ivoire1 (0)
Zaire1994Minkouka, Gabon49 (59)
Zaire1995Kikwit, Zaire315 (77)
Reston1996Alice, Texas, USA0
  Calamba, Philippines 
Zaire1996Makokou and Booué, Gabon91 (73)
  Johannesburg, South Africa 

Because the natural reservoir of filoviruses remains a mystery, one cannot easily predict the occurrence of outbreaks. Efforts to detect Ebola virus in animal specimens from the wild have not been successful. These efforts have been few and too limited to adequately address the problem of identifying the natural host from animals inhabiting the forests. Results of experimental infection of bats indicate they can support the replication of Ebola virus (1995 Zaire isolate) and shed the virus without showing overt signs of disease. Chimpanzees in the wild are known to be naturally infected with Ebola virus, and, from epidemiological investigations in Côte d'Ivoire and Gabon, it would seem likely that other nonhuman primates become infected as well. Ebola virus infections of these nonhuman primates in Africa probably result from direct or indirect contact with the natural host, leading to amplification of the virus and introductions into human populations if these animals are encountered.

During the 1995 Kikwit outbreak, it was noted that secondary transmission occurred only through direct and close contact with patients, and that aerosol transmission did not occur. The spread of disease among humans during some of the outbreaks in Africa, including the 1995 Kikwit episode, was accelerated when cases were treated in local hospitals. The nosocomial spread of disease was attributed to the reuse of contaminated needles and the lack of proper barrier nursing procedures to protect patients and staff from contact with highly infectious body excretions and secretions. These epidemics stopped or were slowed when medical care facilities ceased to function as sources of infectious virus, usually as a result of mortality among the staff or when proper barrier nursing techniques and decontamination practices were established. Because spread of the virus requires contact with infected persons and/or body fluids, the risk of infection is easily decreased by avoiding behaviours that subject persons to such contact.

Patient Management and Control

  1. Top of page
  2. Molecular Biology
  3. Pathology and Pathogenesis
  4. Epidemiology
  5. Patient Management and Control
  6. References
  7. Further Reading

No specific treatment for filovirus haemorrhagic fever is available for use in the event of an outbreak. The antiviral drug ribavirin, which is useful in treating other haemorrhagic fever diseases such as Lassa fever and haemorrhagic fever with renal syndrome (HFRS) due to Hantaan virus, has no effect on filoviruses in vitro and has not been considered for use in infected patients. Experimental treatment of infected monkeys with interferon failed to increase survival of infection. Currently, only supportive care is available for treating patients; the administration of intravenous fluids and/or transfusions may be therapeutic. See also Antiviral Drugs

The development of vaccines against Ebola virus has been slow, and the use of killed virus preparations has not stimulated protective immune responses when evaluated using guinea-pig and monkey models. However, genetic immunization, a technique that uses injections of plasmid deoxyribonucleic acid (DNA) that programmes de novo synthesis of a foreign protein, has proven to be an effective method of inducing protective immune responses in guinea-pigs (Xu et al., 1997). This technique mimics an actual infection by producing newly synthesized protein within antigen-processing cells that stimulate the development of cytotoxic T cells capable of killing Ebola virus-infected cells. Genetic immunization with DNA expressing the GP, SGP or nucleoprotein of the Zaire species of Ebola virus has proven effective in inducing immunity. It remains to be seen if this method of vaccination, as well as other recombinant DNA-based strategies, can be successfully transferred to monkeys and humans. If successful, the development of a safe and protective vaccine would be very important in safeguarding the lives of persons working with Ebola viruses in research facilities and persons at risk during future outbreaks. See also Vaccines: DNA, and Filoviruses

References

  1. Top of page
  2. Molecular Biology
  3. Pathology and Pathogenesis
  4. Epidemiology
  5. Patient Management and Control
  6. References
  7. Further Reading
  • Sanchez A, Kiley MP, Holloway BP and Auperin DD (1993) Sequence analysis of the Ebola virus genome: organization, genetic elements, and comparison with the genome of Marburg virus. Virus Research 29: 215240.
  • Sanchez A, Trappier S, Mahy BWJ, Peters CJ and Nichol ST (1996) The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proceedings of the National Academy of Sciences of the USA 93: 36023607.
  • Sanchez A, Yang Z-Y, Xu L et al. (1998) Biochemical analysis of the secreted and virion glycoproteins of Ebola virus. Journal of Virology 72: 64426447.
  • Volchkov VE, Feldmann H, Volchkova VA, and Klenk H-D (1998) Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proceedings of the National Academy of Sciences of the USA 95: 57625767.
  • Weissenhorn W, Calder LJ, Wharton SA, Skehel JJ and Wiley DC (1998) The central structural feature of the membrane fusion protein subunit from the Ebola virus glycoprotein is a long triple-stranded coiled coil. Proceedings of the National Academy of Sciences of the USA 95: 60326036.
  • Wool-Lewis RJ and Bates P (1998) Characterization of Ebola virus entry using pseudotyped viruses: identification of receptor-deficient cell lines. Journal of Virology 72: 31553160.
  • Xu L, Sanchez A, Yang Z-Y, Nabel EG, Nichol ST and Nabel GJ (1997) Genetic immunization for Ebola virus infection. Nature Medicine 4: 3742.
  • Yang Z-Y, Delgado R, Xu L et al. (1998) Distinct cellular interactions of secreted and transmembrane Ebola virus glycoproteins. Science 279: 10341037.

Further Reading

  1. Top of page
  2. Molecular Biology
  3. Pathology and Pathogenesis
  4. Epidemiology
  5. Patient Management and Control
  6. References
  7. Further Reading
  • Feldmann H, Sanchez A and Klenk H-D (1998) Filoviruses. In: Collier L et al. (eds) Topley & Wilson's Microbiology and Microbial Infections, 9th edn, vol. 1, pp. 651664. London: Arnold.
  • Peters CJ, Sanchez A, Rollin PE, Ksiazek TG and Murphy FA (1996) Filoviridae: Marburg and Ebola viruses. In: Fields BN, Knipe DM, Howley PM et al. (eds) Fields Virology, 3rd edn, pp. 11611176. Philadelphia: Lippincott-Raven.