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Copyright 2005 Tara K. Harper.  All rights reserved.

TKH Virology Notes:
Ebola

 Description       Mechanism       Outbreaks*
 Location       Incubation Period       Vaccine
 Vector       Symptoms      Odds 'n' Ends
      Diagnosis      Links*
      Mortality Rates
      Treatment

*  updated!

Science and Literary  Links for Writers
Science and Technical  References for Writers


NOTE:  This file is for information only.  It is not intended for diagnosis.




Electron micrograph
of ebola (CDC)

.

Ebola
    Ebola Zaire
    Ebola Sudan
    Ebola Reston
    Ebola-Tai
or Ebola Ivory-Coast

Also known as:
    Green monkey fever

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Description.   An acute, infectious, hemorrhagic viral fever.  Ebola is the second member of the family Filoviridae, or "thread" viruses.  It is an enveloped, single-stranded, unsegmented, negative-sense RNA virus.  It has the characteristic filamentous structure of a thread virus:  it can appear shaped like a U, a 6, or coiled like a snail; and can sometimes be branched.  (Refer to Links, at the bottom of this page, for electron micrographs.)  The virus tends to include long, noncoding regions at its 3' and/or 5' ends.  The presence of the noncoding regions probably contributes to the stability of the viral transcript.  This stability, along with the minute differences between glycoproteins (very low genetic drift) in different outbreaks over time, may indicate that the virus has evolved to occupy several niches in the wild.

Ebola virions are 80 nm in diameter, but their length varies greatly, up to 14,000 nm.  Average virion length appears to be approximately 920 nm.  The length associated with greatest infectivity is 970 nm.  

The virions contain seven major structural proteins (such as membrane proteins).  One of those structural proteins is present in two forms.  No other ebola-specific viral proteins have been identified in infected cells.  Virion lipids reflect the composition of lipids in the host-cell membranes.  

Ebola virus is identical to Marburg virus in form and structure; however, it is antigenically distinct from Marburg.

Ebola was named for a small river near Maridi, Sudan.  Since the emergence of filoviruses in 1967, there have been over 1000 cases of Ebola or Marburg, with more than 50% of the patients dying within days on the onset of acute symptoms.  Ebola is classified as a biosafety level 4 agent because of its extreme pathogenicity and the lack of a vaccine or antiviral drug.

Ebola Zaire.  The most highly virulent subtype of Ebola.  Infection usually results in death.  First appeared in 1972, but was not identified until later cases appeared in 1976.

Ebola Sudan.  An extremely pathogenic subtype.  First appeared in 1976 concurrent with the 1976 epidemic of Ebola Zaire.

Ebola Reston.  This subtype originated in Asia and was brought to the U.S. (and to Italy) by infected macaques imported from the Phillippines.  The infected monkeys and their viral samples were received at a lab which investigates viral epidemics, and subsequently, three rooms of monkeys contracted a new strain (Reston) of Ebola. The disease continued to spread within the quarrantine facility even after euthenasia of the monkeys, partly as a result of new shipments of infected animals.  The role of simian hemorrhagic fever, which was also present in most of the imported monkeys, is not completely clear, but mortality among the monkeys from Ebola was estimated at 80%.  The strain has not yet caused disease in humans, although it has infected at least four people.

Ebola-Tai.  A new strain which appeared in 1994 and was isolated as a unique subtype in 1995 at the Institute Pasteur, Paris.  The Tai strain is the first recognized emergence of Ebola in West Africa.

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Location.  Asia and Africa.  One particularly "fertile" area for Ebola is on the border of Kenya and Uganda, in the Mt. Elgon region.  Visitors to the Kitum cave on top of Mt. Elgon have contracted Marburg, while Ebola has been isolated from monkeys in Uganda, within 60 miles of Mt. Elgon.  Many residents of Central Africa (between 2% and 7% of the population tested) have antibodies to Ebola virus.  People in the Haut-Ogooue region of Gabon are routinely exposed to Ebola.

It is possible that the virus has a wide geographic distribution in which monkeys are a significant factor--not as a reservoir, but possibly as a host species to an as-yet unknown arthropod vector.  Studies have shown that 10% of all Asian and African monkeys tested carry Ebola antibodies.

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Vector.  The natural reservoir for Ebola is unknown.  Epidemiologists have tested bats, monkeys, spiders and ticks for the virus, but have not been able to acquire definitive data.  Common factors indicate that the natural reservoir is part of rural Africa, and CDC tests have shown that 10% of all Asian and African monkeys have antibodies to filoviruses.  However, because the virus is as pathogenic in nonhuman primates as it is in humans, it is highly unlikely that monkeys themselves are a reservoir.  It is speculated that persistent mammalian infection may help maintain the virus in nature, but that the natural reservoir is more likely to be a long-lived arthropod associated with the monkeys.

Secondary spread of the disease is via contact with infected persons or contact with blood, secretions, or excretions of infected persons.  However, contact between viremic persons results in infection rates of approximately 10% ---such contact is not an efficient form of viral transmission.  Infection via contact during the incubation period is rare.  In contrast, nosocomial transmission is extremely dangerous.  In all epidemics, nosocomial transmission, via contaminated syringes or needles, was responsible for a significant number of deaths.

In a small number of cases of the Zaire and Sudan strains, patients did not have contact with the blood or body fluids of other viremic patients.  In these few cases, it is possible that the patients contracted the virus via aerosol transmission.  Although the Zaire and Sudan strains are not usually passed from human to human by aerosol, the Reston strain is transmitted via small-particle aerosol between monkeys and from monkeys to humans.  In addition, Ebola Zaire and Marburg virus have been isolated from the alveoli of infected monkeys.

Viruses can persist in injection equipment, multidose medicine vials, or in dried material.  The virus can also continue to be shed in the patient's semen for 3 or 4 months after symptoms disappear.  In one case, the virus was isolated from the anterior chamber fluid of a uveitis patient.  

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Mechanism.   The exact mechanism is unknown.  Systemically, the virus involves the heart, blood vessels, stomach, intestine, liver, lymphoid organs, and kidneys, causing hemorrhaging and in many cases, organ failure.  The host usually dies with no evidence of an immune response.

Some notes on possible mechanisms:  Marburg has 22 potential N-linked glycosylation sites on its surface, and the Ebola virus has 17 potential sites.  Both Marburg and Ebola contain seven genes which code for proteins.  One gene codes for two variations of the same glycoprotein (GP):  a transmembrane glycoprotein (GP) and a smaller (sGP) form.  Marburg virion surface spikes are made soley of this large glycoprotein.  Recent research indicates that Ebola surface spikes are similar.

Both forms of the glycoprotein (large and small forms) are secreted from cells infected by Ebola.  Both proteins are encoded by the same gene (Ebola has only seven genes), but the proteins have different ceullar targets.

The smaller protein (sGP) is at least 300 animo acids smaller than the larger membrane protein.  This smaller protein is secreted in large amounts during early phases of infection.  This smaller protein binds to neutrophils--the white blood cells which trigger inflammation.  It is thought that, by binding to neutrophil receptors, the sGP locks up and halts the inflammatory response which should fight off the virus.  It is possible that doctors could consider ways to provoke neutrophil activity to rouse those cells into better stimulating the immune system.

The other, larger, membrane GP remains bound to the Ebola virus.  This protein forms the surface of the new viruses manufactured in the Ebola-infected cells.  Animal studies show that this GP invades a variety of cell types.  However, it binds preferentially to receptors on endothelial cells--cells which line the inner surfaces of the heart, blood vessels, and other internal organs.  This binding allows the GP surface spikes to mediate entry into susceptible cells, where the virus can begin replicating in the cytoplasm.  As the infected cells secrete additional GP, the protein is used to create the surface (and surface spikes) of newly produced viruses.  The preferential binding to endothelial cells may help explain the extensive coagulopathy caused by the disease.  (Refer to Odds 'n' Ends for a potential application of this membrane protein.)

The proposed mechanisms described here are only hypotheses.  The endothelial-cell receptor to which the GP binds has not yet been identified.  Also, although one deadly strain of Ebola produces severe symptoms and large amounts of soluble GP; another equally deadly strain produces severe symptoms but small amounts of soluble GP.  The glycoprotein might not always be necessary to cause severe symptoms.

Results from the Reston-infected monkeys indicate that there was less endothelial cell involvement with the Reston subtype than with other Ebola subtypes.

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Incubation Period:  3-21 days.  The average incubation period for nosocomial transmission (specifically, needle-transmission) is 5-7 days.  The average incubation period for close-contact transmission is 6-12 days.

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Symptoms.   Sudden onset of fever and malaise, with extreme prostration and weight loss.  Subsequent symptoms include:  sore throat, chest pain, abdominal pain, skin rash, and diarrhea.  The patient's blood fails to clot, and patients may begin to bleed from needle/injection sites as well as into the skin and stomach, intestines, and other internal organs.  Excessive effusions from internal organs occurs, followed by pulmonary interstitial edema and renal dysfunction. Some patients become jaundiced.  About 15% of patients experience hiccups when infected with Ebola Zaire; 38% develop bleeding.  Within 7 to 10 days, patients who will survive begin to recover.  Recovery can take 5 weeks or more, and is marked by prostration, weight loss, and amnesia for the period of acute illness.

Patients who are at greatest risk of dying experience diffuse or extensive hemorrhage into the skin, mucous membranes, and internal organs, including the cavities of the stomach and intestines.  Swelling of the spleen, lymph nodes, kidneys, and brain occurs.  In addition, there is usually evidence of interstitial pneumonia and sometimes of pancreatitis and inflammation in the eyes.  By the end of the first week of acute symptoms, the patient can bleed freely from the eyes, ears, and nose.  Patients begin to vomit a black "sludge" of blood and disintegrated internal organs.  Capillary leakage results in vascular collapse.  Patients experience coma and convulsions, followed by respiratory distress, and finally death.

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Diagnosis.   Diagnosis is confirmed by IgG ELISA.   IgM ELISA can be used to distinguish acute infections from old infections.  IFA is usually highly misleading for Ebola.  Electron microscopy is useful in diagnosing filovirus infection, but does not help distinguish Ebola from the morphologically identical Marburg virus.

Laboratory findings include:
       Maculopapular rash, which is distinctive of Marburg, Ebola, dengue, and lassa.
       Reduction in the number of lymphocytes (lymphopenia) and increased number of neutrophilic leukocytes (neutrophilia).
       Thrombocytopenia and abnormal platelet aggregation.
       Serum enzyme levels are elevated;  AST is usually higher than ALT.
       Alkaline phosphatase and bilirubin levels are usually normal or only mildly elevated.

Ebola can be clearly diagnosed from specimens of deceased patients via immunohistochemistry, virus isolation, or PCR (polymerase chain reaction) of blood or tissue specimens.

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Mortality Rates.  As high as 90%.  This is the mortality rate for infections, not just for clinical illness.  

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Treatment.   Supportive therapy (there is no specific treatment for Ebola).  Fluids pumped into the bloodstream results in death by pulmonary edema, since leaking veins in the lungs flood the airways with fluid.  So far, interferon has had no effect on the virus.

The virus itself is sensitive to lipid solvents, detergents, commercial hypochlorite disinfectants, and phenolic disinfectants.  The virus can also be destroyed by ultraviolet and gamma radiation.

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Outbreaks and History of Human Infection.
   .
Year Location Strain Cases Secondary* Infections
Acquired by
Dead

Mortality

Description
1972 Not avail. EBO-Z

3

contact with 
infected material

2

66%

Investigators believe that two fatal cases occurred, as well as one nonfatal case (confirmed serologically) in which a physician contracted Ebola after performing an autopsy on a patient originally believed to have died from yellow fever.
1976 Zaire EBO-Z

85
43
149

- injection
- infection/contact
- contact

85
39

133

100%
91%
89%

The index case introduced the virus into a hospital in Zaire.  Secondary transmission occurred when others received injections from unsterilized equipment and via contact with viremic patients.  Final reports list the number infected at 318, with 280 deaths.
1976 Sudan EBO-S

284

nosocomial transmission
and contact

150

53%
0%

An independent epidemic from the outbreak in Zaire.  The earliest cases were traced to a cotton factory in Nzara, where the patients had worked in the same room.  The outbreak then spread to nearby towns via nosocomial transmission.  In some cases, the disease was acquired via person-to-person contact in the homes, but only after contact with severely diseased patients.
1976 England EBO-S

1

accidental injection

0

0%

A lab worker accidentally stuck himself with a contaminated needle.
Year Location Strain Cases Secondary* Infections
Acquired by
Dead

Mortality

Description
1977 Tandala,
Zaire
EBO-Z

1

primary

1

100%

A child died with hemorrhagic fever, 195 miles from the original focus in Zaire.
1979 Nzara,
Sudan
EBO-S

34

nosocomial transmission and contact

22

65%

Recurrent outbreak.  The index patient worked in the same room in the cotton factory identified as the focal point for the 1976 epidemic.
1989 Reston, Virginia EBO-R

4

contact with necropsy sample
or unknown

0

0%
0%

Four humans infected with the Ebola strain, but none of them experienced actual disease.  One worker was infected when he cut himself while performing a necropsy on an infected monkey; the other three had no defined exposure to the virus.  A fifth person developed a fever and digestive symptoms, but did not have Ebola.
1994 Gabon EBO-Z

44

not avail

28

64%

Initially thought to be yellow fever, but later identified as Ebola.
1994 Ivory
Coast
EBO-T

1

contact with necropsy sample

0

0%

An ethologist obtained necropsy samples from dead chimpanzees in the Tai forest and, 8 days later, the ethologist developed fever, followed by diarrhea and rash.  The Ebola strain which infected her was serologically unique and has become the new subtype:  Ebola Tai.
1995 Kikwit, Zaire EBO-Z

315

nosocomial transmission
and contact

244

In males: 
81%
In females:
74%
Overall:
77%

Epidemic probably began in January in the savanna and forest. Nosocomial transmission (more than 250 cases with 80% mortality) and close contact with severely ill patients continued to spread the disease.
Year Location Strain Cases Secondary* Infections
Acquired by
Dead

Mortality

Description
1996 Gabon EBO-Z

37

contaminated
meat, plus contact

21

57%

A chimpanzee was found dead in the forest and was eaten; 19 of those involved in butchering the chimp became ill; others became ill via contact with the viremic persons.
1996 Gabon EBO-Z

60

contact

45

75%

Index patient was a hunter; additional cases occurred via contact with viremic persons.
1996 Gabon EBO-Z

2

contact

1

50%

A medical professional contracted Ebola while treating virus-infected patients in Gabon.  A nurse who subsequently cared for him in South Africa became infected and died.
Oct 2001 to Feb 2002 Gabon, Congo Not avail. Not avail. 96 **
Jan 2003 Cuvette-
Ouest in Congo
Not avail. WHO stats:
73

Gov't stats:
80

WHO stats:
59

Gov't stats:
67

The BBC reported that the locals were uncooperative with the medical teams, and that many locals believed the deaths were a result of sorcery or were caused by something the medical teams themselves brought into the area.  At one point, out of 16 confirmed cases, only one person agreed to be hospitalised.  CNN later reported that four teachers were accused of casting a spell to cause the outbreak, and were subsequently stoned and beaten to death.  
Year Location Strain Cases Secondary* Infections
Acquired by
Dead

Mortality

Description
Dec 2003 Congo Not avail. 35 29 83%
May
to
June 26,
2004
Yambio,
southern
Sudan
EBO-S 17 7 23% Initial reports from health authorities were of 30 cases and 7 deaths.  Later lab tests and epidemiological evidence reclassified some cases.  WHO stats are 17 confirmed cases and 7 deaths.
May 2005 Sudan EBO-Z 19 5 26%
May 2005 Central 
Siberia
Not avail. 1 Needle 1 100% While conducting research at Vektor State Research Center of Virology and Biotechnology in Siberia (a top bioweapons facility during the Soviet reign), Russian researcher, Antonina Presnyakova accidentally stuck herself with a needle containing Ebola, and died 14 days later.  This is the third time a Vektor researcher has accidentally infected him/herself with Ebola and has subsequently died.
Jun
2005
Etoumbi and Mbomo,
Cuvette-
Ouest in Congo
Not avail. 12 9 75%

* Nosocomial transmission is common in third-world countries where medical facilities are underfunded and where equipment--even supposedly disposable equipment--is routinely reused without proper sanitation procedures.

** Recent outbreaks of ebola among primates includes a 2004 outbreak in the Republic of Congo, which killed 90 percent of the gorillas in some areas.  The Smithsonian reported in January, 2005, that at the Lossi Gorilla Sanctuary, 139 of 145 gorillas died from Ebola.  

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Vaccine.   None.  As with exposure to other filoviruses, exposure to Ebola does not confer subsequent immunity.  The antibody response in convalescent patients does not neutralize or protect against subsequent infection by Ebola virus.  Researchers are now studying genetic immunization approaches.  One article which may be of interest::  Immunization for Ebola Virus Infection; Nature Medicine, Vol. 4, No. 1, January 1998, 16:17, 37:42.

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Odds 'n' Ends.  
       Marburg and Ebola Zaire viruses have seven sequentially arranged genes contained in a single molecule.  This is the largest genome reported for members of the order Mononegavirales.

       In general, genes of rhabdoviruses and paramyxoviruses are separated by short, intergenic regions.  However, some genes of Marburg and Ebola actually overlap each other.  In the Marburg genome, there is one overlap; in Ebola, there are three overlaps.

       It is possible that the large membrane glycoprotein could be genetically added to a harmless virus.  This would potentially create a vehicle which could carry genes (for gene therapy) directly to endothelial cells.

       From a challenge on a biosci newsgroup (during the Ebola media-hyped terror that seemed to pervade the internet), to write a poem that began with the line: ` "Outbreak" is a movie; "The Hot Zone" is a book...'

        Those Fascinating Filoviridae...

        "Outbreak" is a movie; "The Hot Zone" is a book--
        This hemorrhagic fever sure has the world ashook.
        For all the fascination with Filoviridae,
        More people die from cholera on any given day.
        More die from influenza, TB, and meningitis;
        The hype is just another round of selfish TV-itis.

        It's easy being so concerned when vicariously thrilled
        With all the distant, violent ways that people can be killed.
        So easy just to run your mouth and escalate the scare--
        It's much more fun than studying the info that's out there.
        So read the novels, watch the news, and feel your tensions rise:
        The truth has not the same appeal as titillating lies.

                      - Tara K. Harper

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Links:
       Fact Sheet - Centers for Disease Control (CDC)
       Links to Ebola sites
       More links to Ebola sites


Copyright 2005Tara K. Harper

All rights reserved.  It is illegal to reproduce or transmit in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, any part of this copyrighted file without permission in writing from Tara K. Harper.  Permission to download this file for personal use only is hereby granted by Tara K. Harper.


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