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Ebola Virus
The Ebola Virus is the common name for several strains of virus, three of which are known to cause hemorrhagic fever in humans, which is characterized by massive bleeding and destruction of internal tissues. Named for the Ebola River in Zaire, Africa, where the virus was first identified, the Ebola virus belongs to the family Filoviridae. Three strains of Ebola virus that are often fatal to humans have been identified. Named for the areas in which the first recognized outbreaks took place, these strains are referred to as Ebola/Zaire (EBOZ), Ebola/Sudan (EBOS), and Ebola/Tai Forest (EBOT). A fourth Ebola strain, called Ebola/Reston(EBOR), has not been found to cause disease in humans. As outbreaks of Ebola hemorrhagic fever continue to occur, other strains may be identified. The viruses are long rods, 800 to 1000 nanometers (nm) long (1 nm equals one-billionth of a meter, or 4 x 10-8 in), but particles as long as 14,000 nm have been seen. Each virus consists of a coiled strand of ribonucleic acid (RNA) contained in an envelope derived from the host cell membrane that is covered with 7 nm spikes placed 10 nm apart visible on the surface of the virion (Figure 1). When magnified several thousand times by an electron microscope, these viruses have the appearance of long filaments or threads but the particles are pleomorphic, meaning they can exist in many shapes. Their basic structure is long and filamentious, essentially bacilliform, but the viruses often takes on a "U" shape (Figure 2). They contain a unique single-stranded molecule of noninfectious (negative sense ) RNA. The virus is composed of 7 polypeptides, a nucleoprotein, a glycoprotein, a polymerase and 4 other undesignated proteins. Proteins are produced from polyadenylated monocistronic mRNA a species transcribed from vi genomes. As the infection progresses the cytoplasm of the infected cell develops "prominent inclusion bodies" which contains the viral nucelocapsid, which will become highly structured. The virus then assembles, and buds off the host cell, attaining its lipoprotein coat from the infected cell's outer membrane. The replication in and destruction of the host cell is rapid and produces a large number of viruses budding from the cell membrane. Symptoms Cases of Ebola have occurred in isolated instances and in outbreaks in sub-Saharan Africa. A significant problem in diagnosing the disease is that the viruses often strike in remote areas of developing countries, where access to laboratories for specimen analysis is limited. Of all the Ebola strains, Ebola/Zaire is the most dramatic and deadly. The Ebola virus causes hemorrhagic fever, which is characterized by such symptoms as severe headache, weakness, and muscle aches, followed by vomiting, abdominal pain, diarrhea, inflammation of the throat (pharyngitis), inflammation of the mucous membranes in the eye (conjunctivitis), and bleeding from body openings. The virus spreads through the blood and is replicated in many organs. The histopathologic change is focal necrosis in these organs, including the liver, lymphatic organs, kidneys, ovaries and testes. The central lesions appear to be those affecting the vascular endothelium and the platelets. The resulting manifestations are bleeding, especially in the muc usually seven to ten days. The mortality rates in the known outbreaks have been 60 percent with Ebola/Sudan virus and 77 to 88 percent with Ebola/Zaire virus. Although it is believed that death results directly from the damage to internal tissues, it is not known why some patients manage to survive the disease. There are no proven therapeutic drugs to treat Ebola hemorrhagic fever, and treatment currently consists of preventing shock and providing supportive care. Medical care is complicated by the need to protect medical and nursing personnel. Convalescence is slow, often taking five weeks or more, and is marked by weight loss and amnesia in the early stages of recovery. Currently, there is little hope of developing a vaccine against the Ebola virus. Near the end of one outbreak in Zaire during 1995, blood from convalescent patients was transfused into severely ill victims in an attempt to transfer antibodies and T-lymphocytes (one type of white blood cell) that might neutralize the Ebola virus and destroy infected cells. This procedure met with some success, but carefully controlled trials must be conducted to confirm the safety and effectiveness of this method. Evolution Besides morphological and biochemical similarities, all nonsegmented negative-strand RNA viruses share several features in their mechanisms of transcription and replication: similar genome organization, complementarity of the genome extremities, homologous sequences in the 3' untranslated region, conserved transcriptional signals, interruption of genes by intergenic sequences, possession of a virion-associated polymerase, helical nucleocapsid as the functional template for synthesis of replicative and messenger RNA, replication by synthesis of a full-length antigenome, transcription of messenger RNAs by sequential interrupted synthesis from a single promotor, transcription and replication in the cytoplasm, and maturation by envelopment of independently assembled nucleocapsids at membrane sites containing inserted viral proteins. These data suggest that all nonsegmented negative-strand RNA viruses are derived from a common progenitor and support the classification of the families Filoviridae, Paramyxoviridae and Rhabdoviridae in the order Mononegavirales . In addition, comparative amino acid sequence analyses of nucleoproteins and polymerase proteins suggest that filoviruses are more closely related to paramyxoviruses than to rhabdoviruses. History of Ebola Outbreaks Ebola virus was identified for the first time in 1976, when two epidemics of hemorrhagic fever occurred, one in Zaire, the other 600 km distant in Sudan. The combined outbreaks accounted for more than 550 cases and 430 deaths. A third strain of the Ebola virus was identified in 1989 in a quarantine facility in Reston, Virginia, where hundreds of imported Philippine monkeys died. The Ebola/Reston virus seems not to cause disease in humans-although four laboratory technicians were infected with the virus, none of them became ill. Another large epidemic of Ebola hemorrhagic fever occurred in Zaire, this time in and around the city of Kikwit during the summer of 1995, infecting 315 people and killing 242. The strains of Ebola virus isolated in Zaire in 1976 and 1995, 19 years and 500 km apart, are virtually identical. A single nonfatal case of Ebola hemorrhagic fever occurred in late 1994 in Cte d'Ivoire. A Swiss zoologist who performed an autopsy on a chimpanzee was infected by the virus, which was subsequently identified as the fourth strain, Ebola/Tai Forest, named for the Tai Forest in the Cte d'Ivoire. Since the first episode there have been additional cases and fatalities caused by this virus, in Cte d'Ivoire, Liberia, and Gabon. Diagnosing the Virus Each outbreak has been traced to an index case, an infected person who came into contact with a reservoir host, an animal or arthropod involved in the life cycle of the virus. Of all the disease-causing human viruses, the Ebola and its relative Marburg, which also causes hemorrhagic fever, are the only ones remaining for which the original host and the natural transmission cycle remain unknown. It is not known whether monkeys serve as hosts or if other mammals, birds, reptiles, or even mosquitoes or ticks are involved. >From the index case, infection between humans is principally due to direct, close contact, such as that between a patient and nurses and doctors. Unhygienic hospital conditions also spread the virus. The disease is diagnosed using a laboratory technique called ELISA (enzyme-linked immunosorbant assay) that searches for specific antigens (viral proteins) or antibodies made by the infected patient. The test is performed on a monolayer of infected and uninfected cells fixed on a microscopic slide. IgG- or IgM-specific immunoglobulin assays are performed. These tests may then be confirmed by using western blot or radioimmunoprecipitation. Virus isolation is also a highly useful diagnostic method, and is performed on suitably preserved serum, blood or tissue specimens stored at -70oC or freshly collected. A technique used to duplicate genetic material for study, called the polymerase chain reaction, is used to detect Ebola viral material in patient blood or tissues. When infection by the virus is suspected, local health officials institute strict barrier nursing procedures (such as the use of gowns, gloves, and masks) and usually call on experts from the World Health Organization (WHO), the Centers for Diseas The Ebola virus has been classified by the CDC as Biosafety Level 4, which requires the greatest safety precautions. To ensure maximum safety, virologists must work in special protective clothing, and their laboratories contain equipment that sterilizes air, and liquid and solid wastes. Detailed studies comparing RNA sequences between the different viral strains are only now being performed. It is hoped that such genetic information will provide clues about the natural history and hosts of the viruses. Natural Reservoir The natural reservoir of the Ebola virus is not entirely known. Serological studies suggest that Ebola or related viruses are endemic in Zaire, Sudan, the Central African Republic, Gabon, Nigeria, Ivory Coast, Liberia, Cameroon and Kenya. The geographic range of Ebola strains may extend to other African countries, for which adequate survey is lacking. Extensive ecological studies are currently underway in Cte d'Ivoire, Gabon and Zaire to pinpoint the reservoir. Ebola-related filoviruses were isolated from cynomolgus monkeys (Macacca fascicularis) imported into the United States of America from the Philippines in 1989. A number of the monkeys died and at least four persons were infected, although none of them suffered clinical illness. Annalysis of Outbreaks Serologic evidence has suggested the presence of Ebola virus in Gabon since 1982. Since late 1994, three apparently independent outbreaks of Ebola virus hemorrhagic fever have occurred among humans in northeastern Gabon, in the forested areas of equatorial Ogoou-Ivindo province. The first, which started in December 1994 in gold-panner encampments of far northeastern Gabon, in the Minkouka area (Figure 3) near the Nouna River, had several laboratory-confirmed cases. The second, which began in early February 1996 in Mayibout village (Figure 3) on the Ivindo River, resulted in 37 Ebola hemorrhagic fever cases. The only means of transportation between these two areas is by boat; Makokou, the closest town to them (Figure 3), has the provincial hospital to which patients and contacts were transferred. The third outbreak, started in July 1996 in the village of Boou (Figure 3), where most of the cases occurred; however, scattered cases have been diagnosed in surrounding villages and towns. Some patients have even been transported to Libreville, probably during the incubation period of the disease. One patient was treated in South Africa, where a fatal nosocomial infection was subsequently reported in a health care worker; over 43 deaths due to Ebola hemorrhagic fever were reported during this prolonged outbreak. There were many gene sequences obtained from human samples during each of the three Gabonese epidemics. Some was obtained from blood collected 1 day before the death of a patient, from the Nouna area, during the 1994 outbreak. Other sequences were derived from blood collected during the spring 1996 outbreak, from two primary patients who were infected while butchering a chimpanzee they found dead in the forest. One sequence was derived from blood collected from what appears to have been a secondary case during the same outbreak; the patient was probably infected by contact with one of the index patients while visiting a traditional doctor who lived near Mayibout village. The isolation of Ebola virus in a cell culture from human blood samples collected during the three different outbreaks was easily accomplished in a single passage. RNA was extracted from blood or primary tissue culture samples by using a commercial kit. Viral sequences were amplified from RNA by using the reverse transcriptase-polymerase chain reaction technique. Briefly, amplified products were subjected to agarose electrophoresis and were stained and visualized with ethidium bromide; DNA bands were then excised and extracted. In some cases, nested PCR with internal primers was performed, using first-round products. Amplified products were directly sequenced by using an automated nonisotopic method. Excess dye-labeled dideoxynucleotide terminators were removed, and reaction products were analyzed. A consensus sequence was established by aligning all the Ebola from Gabon, the Zaire 1976 and 1995 Ebola virus sequences, as well as the sequence of the virus obtained from a nurse in South Africa who was infected of the three different outbreaks in Gabon. Although the viruses causing the Gabonese outbreaks clearly belong to the Zaire subtype, they were distinct from viruses that had caused disease in Zaire. No differences were observed between tissue-culture-passaged and clinical-material-derived sequences or between primary or secondary case sequences. RNA extracted from a single representative of each outbreak was then used to generate the entire gene sequence for the Gabon Ebola viruses. The gene sequence from the Gabon spring 1996 viruses differed from the sequence of the Gabon fall 1994 viruses by four nucleotides. The genetic sequence from the Gabon fall 1996 viruses differed from the sequence of the Gabon spring 1996 virus by four additional nucleotides. A single most parsimonious tree was obtained (Figure 4), and bootstrap analysis strongly supports a common evolutionary origin for the viruses associated with disease in Gabon and Zaire. Overall, these data indicate that the three Gabon outbreaks should be considered independent events, likely originating from different sources. The presence of stable virus sequences and the lack of genetic variability between strains isolated within an outbreak was previously seen during the outbreak of Ebola hemorrhagic fever in Kikwit, Zaire, in 1995, and despite the small number of isolates tested, is again suggested in Gabon. During a 20-month period, Gabon had three different outbreaks of Ebola virus hemorrhagic fever. The first and the second episodes apparently started during the rainy season (December and February), while the third began during the dry season (July). The deaths of nonhuman primates were associated with all three outbreaks. Minkouka area inhabitants reported finding dead chimpanzees and gorillas in the forest during the fall of 1994. All the primary human patients in the spring 1996 outbreak were infected while butchering dead chimpanzees. For the third outbreak, the investigation has indicated an index patient who was a hunter, living in a forest camp in the Boou area. During the same period, an Ebola virus-infected dead ch In Cte d'Ivoire in 1994, an investigator was infected with Ebola virus while performing necropsy on a dead chimpanzee. Primates are unlikely to be the reservoir of Ebola virus since experimental or natural infection is quickly fatal. A better knowledge of the ecology of great apes, particularly their food preferences and habitats, may lead to the identification of the virus reservoir. Gabon's equatorial forests, where three independent outbreaks have occurred in less than 3 years, offer an excellent opportunity for these investigations. It has now become apparent that the only solution to this problem, which society is increasingly becoming aware of, is diligent research and experimentation. The CDC continues to inject infant mice and guinea pigs with the virus and document the details of either their deaths or recoveries. It is the hopes of both the scientific community and the rest of the world that some tangible solution be found as soon as possible. Figure 1. Spikes surrounding the virus. Figure 2. The "U" Shape of the virus. Figure 3. Geographic distribution of the three Ebola virus hemorrhagic fever epidemics and site of the infected chimpanzee in Gabon. Figure 4. Phylogenetic tree showing the relationship between the Ebola viruses that caused outbreaks of disease in Gabon and previously described filoviruses. The entire coding region for the glycoprotein gene of the viruses shown was used in maximum parsimony analysis, and a single most parsimonious tree was obtained. Numbers in parentheses indicate bootstrap confidence values for branch points and were generated from 500 replicates Branch length values are also shown. Figure 5. Immunostaining of Ebola virus antigens (red) within vascular endothelial cells in skin biopsy of the chimpanzee found dead in the forest near Boou. Note also the presence of extracellular viral antigens. Bibliography Ebola infections/Ebola-Hemorrhagic-Fever.html. RNA Virus Infections Microsoft Encarta Encyclopedia 97 Ebola Star and Taggart. Biology: The Unity and Diversity of Life. Wadsworth. Toronto.1998 Marburg and Ebola Viruses Centers for Disease Control and Prevention. February 5, 1997 Ebola Page The Outbreak Page


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