Marburg virus | |
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Transmission electron micrograph of Marburg virus | |
Virus classification | |
(unranked): | Virus |
Realm: | Riboviria |
Kingdom: | Orthornavirae |
Phylum: | Negarnaviricota |
Class: | Monjiviricetes |
Order: | Mononegavirales |
Family: | Filoviridae |
Genus: | Marburgvirus |
Species: | |
Virus: | Marburg virus |
Marburg virus (MARV) is a hemorrhagic fever virus of the Filoviridae family of viruses and a member of the species Marburg marburgvirus , genus Marburgvirus . [1] It causes Marburg virus disease in primates, a form of viral hemorrhagic fever. [2] The World Health Organization (WHO) rates it as a Risk Group 4 Pathogen (requiring biosafety level 4-equivalent containment). [3] In the United States, the National Institute of Allergy and Infectious Diseases ranks it as a Category A Priority Pathogen [4] and the Centers for Disease Control and Prevention lists it as a Category A Bioterrorism Agent. [5] It is also listed as a biological agent for export control by the Australia Group. [6]
The virus can be transmitted by exposure to one species of fruit bats or it can be transmitted between people via body fluids through unprotected sex and broken skin. The disease can cause haemorrhage, fever, and other symptoms similar to Ebola, which belongs to the same family of viruses. According to the WHO, there are no approved vaccines or antiviral treatment for Marburg, but early, professional treatment of symptoms like dehydration considerably increases survival chances. [7]
In 2009, expanded clinical trials of an Ebola and Marburg vaccine began in Kampala, Uganda. [8] [9]
Marburg virus was first described in 1967. [12] It was discovered that year during a set of outbreaks of Marburg virus disease in the German cities of Marburg and Frankfurt and the Yugoslav capital Belgrade. Laboratory workers were exposed to tissues of infected grivet monkeys (the African green monkey, Chlorocebus aethiops) at the Behringwerke, a major industrial plant in Marburg which was then part of Hoechst, and later part of CSL Behring. During the outbreaks, thirty-one people became infected and seven of them died. [13]
The virus is one of two members of the species Marburg marburgvirus , which is included in the genus Marburgvirus , family Filoviridae , and order Mononegavirales . The name Marburg virus is derived from Marburg (the city in Hesse, Germany, where the virus was first discovered) and the taxonomic suffix virus. [1]
Marburg virus was first introduced under this name in 1967. [12] The virus name was changed to Lake Victoria marburgvirus in 2005, confusingly making the only difference in distinguishing between a Marburg virus organism and its species as a whole italicization, as in Lake Victoria marburgvirus. [14] [15] [16] Still, most scientific articles continued to use the name Marburg virus. Consequently, in 2010, the name Marburg virus was reinstated and the species name changed. [1]
Like all mononegaviruses, marburg virions contain non-infectious, linear nonsegmented, single-stranded RNA genomes of negative polarity that possess inverse-complementary 3' and 5' termini, do not possess a 5' cap, are not polyadenylated, and are not covalently linked to a protein. [17] Marburgvirus genomes are approximately 19 kbp long and contain seven genes in the order 3'-UTR-NP-VP35-VP40-GP-VP30-VP24-L-5'-UTR. [18]
Like all filoviruses, marburgvirions are filamentous particles that may appear in the shape of a shepherd's crook or in the shape of a "U" or a "6", and they may be coiled, toroid, or branched. [18] Marburgvirions are generally 80 nm in width, but vary somewhat in length. In general, the median particle length of marburgviruses ranges from 795 to 828 nm (in contrast to ebolavirions, whose median particle length was measured to be 974–1,086 nm), but particles as long as 14,000 nm have been detected in tissue culture. [19]
Marburgvirions consist of seven structural proteins. At the center is the helical ribonucleocapsid, which consists of the genomic RNA wrapped around a polymer of nucleoproteins (NP). Associated with the ribonucleoprotein is the RNA-dependent RNA polymerase (L) with the polymerase cofactor (VP35) and a transcription activator (VP30). The ribonucleoprotein is embedded in a matrix, formed by the major (VP40) and minor (VP24) matrix proteins. These particles are surrounded by a lipid membrane derived from the host cell membrane. The membrane anchors a glycoprotein (GP1,2) that projects 7 to 10 nm spikes away from its surface. While nearly identical to ebolavirions in structure, marburgvirions are antigenically distinct. [20]
Niemann–Pick C1 (NPC1) cholesterol transporter protein appears to be essential for infection with both Ebola and Marburg virus. Two independent studies reported in the same issue of Nature showed that Ebola virus cell entry and replication requires NPC1. [21] [22] When cells from patients lacking NPC1 were exposed to Ebola virus in the laboratory, the cells survived and appeared immune to the virus, further indicating that Ebola relies on NPC1 to enter cells. This might imply that genetic mutations in the NPC1 gene in humans could make some people resistant to one of the deadliest known viruses affecting humans. The same studies described similar results with Marburg virus, showing that it also needs NPC1 to enter cells. [21] [22] Furthermore, NPC1 was shown to be critical to filovirus entry because it mediates infection by binding directly to the viral envelope glycoprotein [22] and that the second lysosomal domain of NPC1 mediates this binding. [23]
In one of the original studies, a small molecule was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1. [22] [24] In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse-adapted Ebola virus. [21]
The Marburg virus life cycle begins with virion attachment to specific cell-surface receptors, followed by fusion of the virion envelope with cellular membranes and the concomitant release of the virus nucleocapsid into the cytosol.[ citation needed ]
The virus RdRp partially uncoats the nucleocapsid and transcribes the genes into positive-stranded mRNAs, which are then translated into structural and nonstructural proteins. Marburgvirus L binds to a single promoter located at the 3' end of the genome. Transcription either terminates after a gene or continues to the next gene downstream. This means that genes close to the 3' end of the genome are transcribed in the greatest abundance, whereas those toward the 5' end are least likely to be transcribed. The gene order is therefore a simple but effective form of transcriptional regulation. [25]
The most abundant protein produced is the nucleoprotein, whose concentration in the cell determines when L switches from gene transcription to genome replication. Replication results in full-length, positive-stranded antigenomes that are in turn transcribed into negative-stranded virus progeny genome copies. Newly synthesized structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane. Virions bud off from the cell, gaining their envelopes from the cellular membrane they bud from. The mature progeny particles then infect other cells to repeat the cycle. [14]
In 2009, the successful isolation of infectious MARV was reported from caught healthy Egyptian fruit bats (Rousettus aegyptiacus). [26] This isolation, together with the isolation of infectious RAVV, [26] strongly suggests that Old World fruit bats are involved in the natural maintenance of marburgviruses. Further studies are necessary to establish whether Egyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. In 2012 the first experimental infection study of Rousettus aegyptiacus with MARV provided further insight into the possible involvement of these bats in MARV ecology. [27]
Experimentally infected bats developed relatively low viremia lasting at least five days, but remained healthy and did not develop any notable gross pathology. The virus also replicated to high titers in major organs (liver and spleen), and organs that might possibly be involved in virus transmission (lung, intestine, reproductive organs, salivary gland, kidney, bladder, and mammary gland). The relatively long period of viremia noted in this experiment could possibly also facilitate mechanical transmission by blood sucking arthropods in addition to infection of susceptible vertebrate hosts by direct contact with infected blood. [27]
The viral strains fall into two clades: Ravn virus and Marburg virus. [28] The Marburg strains can be divided into two: A and B. The A strains were isolated from Uganda (five from 1967), Kenya (1980) and Angola (2004–2005) while the B strains were from the Democratic Republic of the Congo epidemic (1999–2000) and a group of Ugandan isolates isolated in 2007–2009. [25]
The mean evolutionary rate of the whole genome was 3.3 × 10−4 substitutions/site/year (credibility interval 2.0–4.8). The Marburg strains had a mean root time of the most recent common ancestor of 177.9 years ago (95% highest posterior density 87–284) suggesting an origin in the mid 19th century. In contrast, the Ravn strains origin dated back to a mean 33.8 years ago (the early 1980s). The most probable location of the Marburg virus ancestor was Uganda whereas that of the RAVV ancestor was Kenya.[ citation needed ]
MARV is one of two Marburg viruses that causes Marburg virus disease (MVD) in humans (in the literature also often referred to as Marburg hemorrhagic fever, MHF). The other one is Ravn virus (RAVV). Both viruses fulfill the criteria for being a member of the species Marburg marburgvirus because their genomes diverge from the prototype Marburg marburgvirus or the Marburg virus variant Musoke (MARV/Mus) by <10% at the nucleotide level. [1]
Year | Geographic location | Virus | Human cases | Human deaths | Case fatality rate | Notes |
---|---|---|---|---|---|---|
1967 | Marburg and Frankfurt, West Germany, and Belgrade, Socialist Federal Republic of Yugoslavia | MARV | 31 | 7 | 23% | Laboratory leak [29] [12] [30] [31] [32] [33] [34] [35] [36] [ excessive citations ] |
1975 | Rhodesia and Johannesburg, South Africa | MARV | 3 | 1 | 33% | [37] [38] [39] |
1980 | Kenya | MARV | 2 | 1 | 50% | [40] |
1987 | Kenya | RAVV | 1 | 1 | 100% | [41] [42] |
1988 | Koltsovo, Soviet Union | 1 | 1 | 100% | Laboratory accident [43] | |
1990 | Koltsovo, Soviet Union | MARV | 1 | 1 | 100% | Laboratory accident [44] |
1998–2000 | Durba and Watsa, Democratic Republic of the Congo | MARV & RAVV | 154 | 128 | 83% | Two different marburgviruses, MARV and Ravn virus (RAVV), cocirculated and caused disease. The number of cases and deaths due to MARV or RAVV infection have not been reported. [45] [46] [47] |
2004–2005 | Angola | MARV | 374 | 329 | 90% | [48] [49] [50] [51] [52] [53] [54] [ excessive citations ] |
2007 | Uganda | MARV & RAVV | 4 | 1 | 25% | [26] [55] |
2008 | Uganda and The Netherlands | MARV | 1 | 1 | 100% | [56] |
2012 | Uganda | MARV | 18 | 9 | 50% | [57] |
2014 | Uganda | MARV | 1 | 1 | 100% | [58] [59] |
2017 | Uganda | MARV | 3 | 3 | 100% | [60] |
2021 | Guinea | MARV | 1 | 1 | 100% | The Guinean government detected the case from a sample of patients who died on August 2, 2021, in the southern prefecture of Gueckedou near the country's borders with Sierra Leone and Liberia. [61] [62] [63] |
2022 | Ghana | MARV | 4 | 3 | 75% | Four cases have been reported so far with preparations for a possible outbreak being made. On 17 July 2022, two cases were confirmed by Ghana, [64] with two more being subsequently confirmed on 27 July 2022. [65] |
February 2023 | Equatorial Guinea | 25 | 11 | 44% | See 2023 Marburg virus disease outbreak in Equatorial Guinea. [67] [68] | |
March 2023 | Tanzania | 8 | 5 | 63% | See 2023 Marburg virus disease outbreak in Tanzania. [69] | |
September 2024 | Rwanda | 26 | 8 | The outbreak was confirmed on September 27. [70] |
The first clinical study testing the efficacy of a Marburg virus vaccine was conducted in 2014. The study tested a DNA vaccine and concluded that individuals inoculated with the vaccine exhibited some level of antibodies. However, these vaccines were not expected to provide definitive immunity. [71] Several animal models have shown to be effective in the research of Marburg virus, such as hamsters, mice, and non-human primates (NHPs). Mice are useful in the initial phases of vaccine development as they are ample models for mammalian disease, but their immune systems are still different enough from humans to warrant trials with other mammals. [72] Of these models, the infection in macaques seems to be the most similar to the effects in humans. [73] A variety of other vaccines have been considered. Virus replicon particles (VRPs) were shown to be effective in guinea pigs, but lost efficacy once tested on NHPs. Additionally, an inactivated virus vaccine proved ineffective. DNA vaccines showed some efficacy in NHPs, but all inoculated individuals showed signs of infection. [74]
Because Marburg virus and Ebola virus belong to the same family, Filoviridae, some scientists have attempted to create a single-injection vaccine for both viruses. This would both make the vaccine more practical and lower the cost for developing countries. [75] Using a single-injection vaccine has shown to not cause any adverse reactogenicity, which the possible immune response to vaccination, in comparison to two separate vaccinations. [71]
As of June 23, 2022, researchers working with the Public Health Agency of Canada conducted a study which showed promising results of a recombinant vesicular stomatitis virus (rVSV) vaccine in guinea pigs, entitled PHV01. According to the study, inoculation with the vaccine approximately one month prior to infection with the virus provided a high level of protection. [76]
Even though there is much experimental research on Marburg virus, there is still no prominent vaccine. Human vaccination trials are either ultimately unsuccessful or are missing data specifically regarding Marburg virus. [77] Due to the cost needed to handle Marburg virus at qualified facilities, the relatively few number of fatalities, and lack of commercial interest, the possibility of a vaccine has simply not come to fruition. [78]
The Soviet Union had an extensive offensive and defensive biological weapons program that included MARV. [79] At least three Soviet research institutes had MARV research programs during the Cold War: The Virology Center of the Scientific-Research Institute for Microbiology in Zagorsk (today Sergiev Posad), the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, and the Irkutsk Scientific-Research Anti-Plague Institute of Siberia and the Far East in Irkutsk. [79]
As most performed research was highly classified, it remains unclear how successful the MARV program was. However, Soviet defector Ken Alibek claimed that a weapon filled with MARV was tested at the Stepnogorsk Scientific Experimental and Production Base in Stepnogorsk, Kazakh Soviet Socialist Republic (today Kazakhstan), [79] suggesting that the development of a MARV biological weapon had reached advanced stages. Independent confirmation for this claim is lacking. At least one laboratory accident with MARV, resulting in the death of Koltsovo researcher Nikolai Ustinov, occurred during the Cold War in the Soviet Union and was first described in detail by Alibek. [79]
MARV is a select agent under US law. [80]
Marburg virus disease (MVD), formerly Marburg hemorrhagic fever (MHF) is a viral hemorrhagic fever in human and non-human primates caused by either of the two Marburgviruses: Marburg virus (MARV) and Ravn virus (RAVV). Its clinical symptoms are very similar to those of Ebola virus disease (EVD).
Filoviridae is a family of single-stranded negative-sense RNA viruses in the order Mononegavirales. Two members of the family that are commonly known are Ebola virus and Marburg virus. Both viruses, and some of their lesser known relatives, cause severe disease in humans and nonhuman primates in the form of viral hemorrhagic fevers.
The genus Marburgvirus is the taxonomic home of Marburg marburgvirus, whose members are the two known marburgviruses, Marburg virus (MARV) and Ravn virus (RAVV). Both viruses cause Marburg virus disease in humans and nonhuman primates, a form of viral hemorrhagic fever. Both are select agents, World Health Organization Risk Group 4 Pathogens, National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogens, Centers for Disease Control and Prevention Category A Bioterrorism Agents, and are listed as Biological Agents for Export Control by the Australia Group.
The genus Ebolavirus is a virological taxon included in the family Filoviridae, order Mononegavirales. The members of this genus are called ebolaviruses, and encode their genome in the form of single-stranded negative-sense RNA. The six known virus species are named for the region where each was originally identified: Bundibugyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, Zaire ebolavirus, and Bombali ebolavirus. The last is the most recent species to be named and was isolated from Angolan free-tailed bats in Sierra Leone. Each species of the genus Ebolavirus has one member virus, and four of these cause Ebola virus disease (EVD) in humans, a type of hemorrhagic fever having a very high case fatality rate. The Reston virus has caused EVD in other primates. Zaire ebolavirus has the highest mortality rate of the ebolaviruses and is responsible for the largest number of outbreaks of the six known species of the genus, including the 1976 Zaire outbreak and the outbreak with the most deaths (2014).
Viral hemorrhagic fevers (VHFs) are a diverse group of animal and human illnesses. VHFs may be caused by five distinct families of RNA viruses: the families Filoviridae, Flaviviridae, Rhabdoviridae, and several member families of the Bunyavirales order such as Arenaviridae, and Hantaviridae. All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in many cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica, while others, such as Ebola virus, can cause severe, life-threatening disease.
Mayinga N'Seka was a nurse in Zaïre, now Democratic Republic of the Congo. She died from Ebola virus disease during the 1976 epidemic in Zaïre. She has been incorrectly identified as the index case by several sources, but a World Health Organization commission report on the outbreak lists a man from Yambuku, Mabalo Lokela, as the index case. Lokela, a 44-year-old who had been buying meat in Sudan, died on September 8, 1976, over a month before N'Seka.
Lisa Ellen Hensley is the associate director of science at the Office of the Chief Scientist, National Institute of Allergy and Infectious Disease Integrated Research Facility in Frederick, Maryland. She was previously a civilian microbiologist in the virology division of the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). Hensley is one of the premier researchers of some of the world's most dangerous infections, including Ebola hemorrhagic fever, Lassa fever, the coronavirus diseases Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and smallpox. She has been involved in research uncovering critical mechanisms in the pathogenesis of hemorrhagic fever viruses, and has used those discoveries to develop candidate therapeutic drugs for their treatment.
The species Lloviu cuevavirus is the taxonomic home of a virus that forms filamentous virion, Lloviu virus (LLOV). The species is included in the genus Cuevavirus. LLOV is a distant relative of the commonly known Ebola virus and Marburg virus.
The species Bundibugyo ebolavirus is the taxonomic home of one virus, Bundibugyo virus (BDBV), that forms filamentous virions and is closely related to the infamous Ebola virus (EBOV). The virus causes severe disease in humans in the form of viral hemorrhagic fever and is a Select agent, World Health Organization Risk Group 4 Pathogen, National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogen, Centers for Disease Control and Prevention Category A Bioterrorism Agent, and is listed as a Biological Agent for Export Control by the Australia Group.
The species Taï Forest ebolavirus is a virological taxon included in the genus Ebolavirus, family Filoviridae, order Mononegavirales. The species has a single virus member, Taï Forest virus (TAFV). The members of the species are called Taï Forest ebolaviruses.
The species Sudan ebolavirus is a virological taxon included in the genus Ebolavirus, family Filoviridae, order Mononegavirales. The species has a single virus member, Sudan virus (SUDV). The members of the species are called Sudan ebolaviruses. It was discovered in 1977 and causes Ebola clinically indistinguishable from the ebola Zaire strain, but is less transmissible than it. Unlike with ebola Zaire there is no vaccine available.
Reston virus (RESTV) is one of six known viruses within the genus Ebolavirus. Reston virus causes Ebola virus disease in non-human primates; out of all 6 ebolaviruses, it is one of the only two not known to cause disease in humans, but has caused asymptomatic infections. Reston virus was first described in 1990 as a new "strain" of Ebola virus (EBOV). It is the single member of the species Reston ebolavirus, which is included into the genus Ebolavirus, family Filoviridae, order Mononegavirales. Reston virus is named after Reston, Virginia, US, where the virus was first discovered.
Ravn virus is a close relative of Marburg virus (MARV). RAVV causes Marburg virus disease in humans and nonhuman primates, a form of viral hemorrhagic fever. RAVV is a Select agent, World Health Organization Risk Group 4 Pathogen, National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogen, Centers for Disease Control and Prevention Category A Bioterrorism Agent, and listed as a Biological Agent for Export Control by the Australia Group.
Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after infection. The first symptoms are usually fever, sore throat, muscle pain, and headaches. These are usually followed by vomiting, diarrhoea, rash and decreased liver and kidney function, at which point some people begin to bleed both internally and externally. It kills between 25% and 90% of those infected – about 50% on average. Death is often due to shock from fluid loss, and typically occurs between six and 16 days after the first symptoms appear. Early treatment of symptoms increases the survival rate considerably compared to late start. An Ebola vaccine was approved by the US FDA in December 2019.
Zaire ebolavirus, more commonly known as Ebola virus, is one of six known species within the genus Ebolavirus. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and other mammals, known as Ebola virus disease (EVD). Ebola virus has caused the majority of human deaths from EVD, and was the cause of the 2013–2016 epidemic in western Africa, which resulted in at least 28,646 suspected cases and 11,323 confirmed deaths.
Recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV), also known as Ebola Zaire vaccine live and sold under the brand name Ervebo, is an Ebola vaccine for adults that prevents Ebola caused by the Zaire ebolavirus. When used in ring vaccination, rVSV-ZEBOV has shown a high level of protection. Around half the people given the vaccine have mild to moderate adverse effects that include headache, fatigue, and muscle pain.
On 11 May 2017, the Democratic Republic of the Congo (DRC) was identified by the World Health Organization (WHO) as having one Ebola-related death.
The 2017 Uganda Marburg virus outbreak was confirmed by the World Health Organization (WHO) on 20 October 2017 after there had been an initial fatality due to the virus.
The 1967 Marburg virus disease outbreak was the first recorded outbreak of Marburg virus disease. It started in early August 1967 when 30 people became ill in the West German towns of Marburg and Frankfurt and later two in Belgrade, Yugoslavia. The infections were traced back to three laboratories in the separate locations which received a shared shipment of infected African green monkeys. The outbreak involved 25 primary Marburg virus infections and seven deaths, and six non-lethal secondary cases.
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