Ebola

Ebola virus
Virus classification
Group:	Group V ((−)ssRNA)
Order:	Mononegavirales
Family:	Filoviridae
Genus:	Ebolavirus
Species:	Reston ebolavirus Sudan ebolavirus Ivory Coast ebolavirus Zaïre ebolavirus

Ebola is the common term for a group of viruses belonging to genus Ebolavirus, family Filoviridae, which cause Ebola hemorrhagic fever. The disease can be lethal and encompasses a range of symptoms, usually including vomiting, diarrhea, general body pain, internal and external bleeding, and fever. Mortality rates are generally high, ranging from 50% - 90%, with the cause of death usually due to hypovolemic shock or multiple organ failure.

Ebola is believed to be a zoonotic virus, although despite considerable effort by the World Health Organization no animal reservoir capable of sustaining the virus between outbreaks has been identified. One candidate reservoir is the fruit bat^[1]. The virus is named after the Ebola River in the African state of the Democratic Republic of the Congo (formerly Zaïre), near the site of the first outbreaks.

Due to its high lethality and the fact that no approved vaccine or treatment is available, Ebola is classified as a biosafety level 4 organism; as well as a category A bioterrorism agent and a select agent by the CDC.

It is traditional to name viral species after the locations in which they were first discovered. The first documented outbreaks of Ebola occurred in the Democratic Republic of the Congo and Sudan in 1976, resulting in the virus being named for a tributary of the Congo River so that it might represent both outbreaks. Two species were further identified later that year: Zaïre ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV) with case-fatality rates of 83% and 54%, respectively. The first electronmicrograph of Ebola was also obtained in 1976 by Dr. F.A. Murphy, who was then working at the Center for Disease Control.

A third species, Reston ebolavirus (REBOV), was discovered in November 1989 in a group of monkeys (Crab-eating Macaque Macaca fascicularis) imported from the Philippines to the United States of America. A new species was identified from a single human case in Côte d’Ivoire in 1994, and named Ivory Coast ebolavirus (ICEBOV).

Further outbreaks have occurred in the Democratic Republic of the Congo (1995, 2001/2002, 2003, 2005), Gabon (1994 - 1996 and 2002), Sudan (2004) and Uganda (2000). In 2003, 128 people died in the Couvette-Ouest Region ^[2], Democratic Republic of Congo, which has been the site of four recent outbreaks, including one in May 2005.

Electron micrographs of members of Ebolavirus show them to have the characteristic filamentous structure of a filovirus. The viral filaments are variable in shape and may appear as a "U", "6", coiled, circular, or branched shape. Laboratory purification techniques, such as centrifugation, may contribute to the various shapes seen. Virions are generally 80 nm in diameter and variable in length, they can be up to 1400 nm long. On average however, the length of a typical ebolavirus is closer to 1000 nm. The nucleocapsid found in the center of the virions is formed by the helically wound viral genomic RNA complexed with the proteins NP, VP35, VP30 and L. It has a diameter of 40 – 50 nm and contains a a central channel of 20 – 30 nm in diameter. Virally encoded glycoprotein (GP) spikes 10 nm long and 10 nm apart are present on the outer viral envelope of the virion, which is derived from the host cell membrane. Between envelope and nucleocapsid, in the so called matrix space, the viral proteins VP40 and VP24 are located.

Each virion contains one molecule of linear, single-stranded, negative-sense RNA, totalling 18900 nucleotides in length. The 3’ terminus is not polyadenylated and the 5’ end is not capped. It codes for seven structural proteins and one non-structural protein. The gene order is 3' - leader - NP - VP35 - VP40 - GP/sGP - VP30 - VP24 - L - trailer - 5'; with the leader and trailer being non-transcribed regions which carry important signals to control transcription, replication and packaging of the viral genome into new virions. The genomic material by itself is not infectious, because viral proteins, among them the RNA-dependent RNA polymerase, are necessary to transcribe the viral genome into mRNAs, as well as for replication of the viral genome.

Ebola viruses contain seven structural proteins. The nucleocapsid proteins NP, VP35, VP30 and L are involved in transcription and replication of the viral genome. NP encapsidates the genomic RNA and is a major structural component of the nucleocapsid. L, the (RNA-dependent RNA polymerase), produces mRNAs and copies the negative-sense genome first into a positive-sense antigenome and then this antigenome back into negative-sense genomes, thus replicating the genomic information. VP35 serves as a cofactor for L, and VP30 is a viral transcription factor. The major matrix protein VP40 is crucial for assembly and budding of new virions. VP24, the minor matrix protein, has been shown to be involved in assembly of nucleocapsids, although VP24 itself is not part of them. Trimers of the glycoprotein (GP) form spikes at the surface of the virions, which have been shown to mediate attachment of virions to target cells as well as fusion of the virus membrane with the target cell membrane. The mRNA for GP is produced after transcriptional editing, which involves the addition of an Adenosine into the mRNA, which is not encoded in the viral genome. If this editing does not occur, the non-structural protein sGP is produced, the function of which is as of 2006 unknown. As a secondary function, both VP35 and VP24 impair the function of the immune system; VP35 impairs the production of Interferon, while VP24 blocks the effects of interferon.

The Zaïre ebolavirus is the most deadly member of the ebolaviruses, with up to a 90% mortality rate in some epidemics, with an average of approximately 83% mortality over 27 years. The case-fatality rates were 88% in 1976, 100% in 1977, 59% in 1994, 81% in 1995, 73% in 1996, 80% in 2001-2002 and 90% in 2003. There have been more outbreaks of Zaïre ebolavirus than any other strain.

The first outbreak took place on August 26, 1976 in Yambuku, a town in the north of the Democratic Republic of the Congo. The first recorded case is Mabalo Lokela, a 44-year-old schoolteacher returning from a trip around the north of the state. His high fever was diagnosed as possible malaria and he was subsequently given a quinine shot. Lokela returned to the hospital every day. A week later, his symptoms included uncontrolled vomiting, bloody diarrhea, headache, dizziness, and trouble breathing. Later, he began bleeding from his nose, mouth, and rectum. Mabalo Lokela died on September 8, 1976, roughly 14 days after the onset of symptoms.

Soon after, more patients arrived with varying but similar symptoms including fever, headache, muscle and joint aches, fatigue, nausea and dizziness. These often progressed to bloody diarrhea, severe vomiting, and bleeding from the nose, mouth, and rectum. The initial transmission was believed to be due to reuse of the needle for Lokela’s injection without sterilization. Subsequent transmission was also due to care of the sick patients without barrier nursing and the traditional burial preparation method, which involved washing and gastrointestinal tract cleansing.

The most recent outbreak of Sudan ebolavirus occurred in May 2004. As of May 2004, 20 cases of Sudan ebolavirus were reported in Yambio County, Sudan, with 5 deaths resulting. The Centers for Disease Control and Prevention confirmed the virus a few days later. The neighboring countries of Uganda and the Democratic Republic of Congo have increased surveillance in bordering areas, and other similar measures have been taken to control the outbreak. The average fatality rates for Sudan ebolavirus were 53% in 1976, 68% in 1979, and 53% in 2000/2001. The average case-fatality rate is 53.76%.

First discovered in November of 1989 in a group of 100 Crab-eating Macaques (Macaca fascicularis) imported from the Philippines to Reston, Virginia. A parallel infected shipment was also sent to Philadelphia. This strain was highly lethal in monkeys, but did not cause any fatalities in humans. Six of the Reston primate handlers tested positive for the virus, two due to previous exposure.

Further Reston ebolavirus infected monkeys were shipped again to Reston, and Alice, Texas in February of 1990. More Reston ebolavirus infected monkeys were discovered in 1992 in Siena, Italy and in Texas again in March 1996. A high rate of co-infection with Simian Hemorrhagic Fever (SHF) was present in all infected monkeys. No human illness has resulted from these two outbreaks.

This species of Ebola was first discovered amongst chimpanzees of the Tai Forest in Cote d'Ivoire, Africa. On November 1, 1994, the corpses of two chimpanzees were found in the forest. Necropsies showed blood within the heart to be liquid and brown, no obvious marks seen on the organs, and one presented lungs filled with liquid blood. Studies of tissues taken from the chimps showed results similar to human cases during the 1976 Ebola outbreaks in Zaire and Sudan. Later in 1994, more dead chimpanzees were discovered, with many testing positive to Ebola using molecular techniques. The source of contamination was believed to be the meat of infected Western Red Colobus monkeys, which the chimpanzees preyed upon.^[3]

One of the scientists performing the necropsies on the infected chimpanzees contracted Ebola. She developed syndromes similar to a dengue fever approximately a week after the necropsy and was transported to Switzerland for treatment. After two weeks she was discharged from hospital, and was fully recovered six weeks after the infection.

The viral attachment protein recognizes specific receptors, which may be protein, carbohydrate or lipid, on the outside of the cell. The mechanism of virus entry into host cells is unknown, but it is reasonable to assume that the glycoprotein spikes on the surface of the virion would mediate the process, as they are the only transmembrane protein present on the surface.

The virus next activates and releases its own genetic material, causing the host to begin manufacturing the proteins necessary for virus reproduction using its own resources. This replication continues until the cell ruptures and bursts. The virus is then spread to neighbouring cells, and continues this chain of reproduction until masses of host cells are damaged. The host dies soon after. The spread of the virus through the population can be halted if the proper sterilization and quarantine measures are taken, as the only method by which the virus may continue to propagate is via direct contact with body fluids.

Symptoms are varied and often appear suddenly. Initial symptoms include: high fever (at least 38.8°C/101°F), severe headache, muscle, joint or abdominal pain, severe weakness and exhaustion, sore throat, nausea, and dizziness. Before an epidemic is suspected, these early symptoms are easily mistaken for malaria, typhoid fever, dysentery, influenza, or various bacterial infections, which are all far more common.

Ebola goes on to cause diarrhea, dark or bloody stools, vomiting blood, red eyes from swollen blood vessels, red spots on the skin from subcutaneous bleeding, maculopapular rash, purpura, and bleeding internally and externally from any orifice, including from the nose, mouth, rectum, genitals or needle puncture sites.

Other secondary symptoms include hypotension (less than 90mm Hg), hypovolemia, tachycardia, severe organ damage (especially the kidneys, spleen, and liver) as a result of necrosis, and proteinuria. The span of time from onset of symptoms to death (usually due to hypovolemic shock and/or multiple organ failure) is usually between 7 and 14 days. By the second week of infection, patients will either defervesce (the fever will lessen) or undergo systemic multiorgan failure.

Among humans, the virus is transmitted by direct contact with infected body fluids, or to a lesser extent, skin or mucus membrane contact. The incubation period can be anywhere from 2 to 21 days, but is generally between 5 and 10 days.

Although airborne transmission between monkeys has been demonstrated in a laboratory, there is very limited evidence for human-to-human airborne transmission in any reported epidemics.^16,17,18 Nurse Mayinga might represent the only possible case. The means by which she contracted the virus remain uncertain.

So far all epidemics of Ebola have occurred in sub-optimal hospital conditions, where practices of basic hygiene and sanitation are often either luxuries or unknown to caretakers and where disposable needles and autoclaves are unavailable or too expensive. In modern hospitals with disposable needles and knowledge of basic hygiene and barrier nursing techniques, Ebola rarely spreads on such a large scale.

In the early stages, Ebola may not be highly contagious. Contact with someone in early stages may not even transmit the disease. As the illness progresses, bodily fluids from diarrhea, vomiting, and bleeding represent an extreme biohazard. Due to lack of proper equipment and hygienic practices, large scale epidemics occur mostly in poor, isolated areas without modern hospitals and/or well-educated medical staff. Many areas where the infectious reservoir exists have just these characteristics. In such environments all that can be done is to immediately cease all needle sharing or use without adequate sterilization procedures, to isolate patients, and to observe strict barrier nursing procedures with the use of a medical rated disposable face mask, gloves, goggles, and a gown at all times. This should be strictly enforced for all medical personnel and visitors.

Treatment is primarily supportive and includes minimizing invasive procedures, balancing electrolytes, replacing lost coagulation factors to help stop bleeding, maintaining their oxygen and blood levels and treating them for any complicating infections. Despite some initial anecdotal evidence, blood serum from Ebola survivors has been shown to be ineffective in treating the virus. Interferon is also thought to be ineffective. In monkeys, administration of an inhibitor of coagulation (rNAPc2) has shown some benefit, protecting 33% of infected animals from a for monkeys usually 100% lethal infection. In early 2006, scientists at USAMRIID announced a 75% recovery rate after infecting four rhesus monkeys with Ebola virus and administering antisense drugs^[4].

Vaccines have been produced for both Ebola and Marburg that were 100% effective in protecting a group of monkeys from the disease^[5]. These vaccines are based on either a recombinant Vesicular stomatitis virus or a recombinant Adenovirus ^[6] carrying the Ebola spikeprotein on its surface. Early human vaccine efforts, like the one at NIAID in 2003, have so far not reported any successes^[7].

Ebola has served as a rich source of ideas and plotlines for many forms of entertainment. The infatuation with the virus is likely due to the high mortality rate of its victims, its mysterious nature, and its tendency to cause gruesome bleeding from body orifices.

Much of the representation of the Ebola virus in fiction and the media is considered exaggerated or myth. Many of the stories about Ebola in Preston's book The Hot Zone are refuted in the book "Level 4: Virus Hunters of the CDC" by Joseph B. McCormick, an employee of the CDC at the time of the early outbreaks. One pervasive myth follows that the virus kills so fast that it has little time to spread. Victims die very soon after contact with the virus. In reality, the incubation time is usually about a week. The average time from onset of early symptoms to death varies in the range 3-21 days, with a mean of 10.1.

Another myth states that the symptoms of the virus are horrifying beyond belief. Victims of Ebola suffer from squirting blood, liquifying flesh, zombie-like faces and dramatic projectile bloody vomiting. In actual fact, only a fraction of Ebola victims have severe bleeding that would be even somewhat dramatic to witness. Approximately 10% of patients suffer some bleeding, but this is often internal or subtle, such as bleeding from the gums. Ebola symptoms are usually limited to extreme exhaustion, vomiting, diarrhea, abdominal pain, a high fever, headaches and other body pains. The following is an excerpt from an interview with Philippe Calain, M.D. Chief Epidemiologist, CDC Special Pathogens Branch, Kikwit 1995:

At the end of the disease the patient does not look, from the outside, as horrible as you can read in some books. They are not melting. They are not full of blood. They're in shock, muscular shock. They are not unconscious, but you would say 'obtunded', dull, quiet, very tired. Very few were hemorrhaging. Hemorrhage is not the main symptom. Less than half of the patients had some kind of hemorrhage. But the ones that bled, died.

• Bolivian hemorrhagic fever
• Crimean Congo hemorrhagic fever (CCHF)
• Marburg hemorrhagic fever, the first known filovirus disease

• Ebola cases and outbreaks – Centers for Disease Control and Prevention
• Ebola Virus Haemorrhagic Fever - a comprehensive overview of the disease
• Death Called a River - Jason Socrates Bardi, Scripps Research Institute
• What is the probability of a dangerous strain of Ebola mutating and becoming airborne? ­ Brett Russel, retrieved 10 July 2006
• WHO Factsheet - general information on the virus, retrieved 10 July 2006