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Marburg virus (MARV) is a
hemorrhagic fever virus Viral hemorrhagic fevers (VHFs) are a diverse group of animal and human illnesses in which fever and hemorrhage are caused by a viral infection. VHFs may be caused by five distinct families of RNA viruses: the families ''Filoviridae'', '' Fl ...
of the '' Filoviridae'' family of viruses and a member of the species ''
Marburg marburgvirus 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 primate ...
'', genus ''
Marburgvirus 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 prim ...
''. It causes Marburg virus disease in primates, a form of viral hemorrhagic fever. The virus is considered to be extremely dangerous. The
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
(WHO) rates it as a Risk Group 4 Pathogen (requiring biosafety level 4-equivalent containment). In the United States, the National Institute of Allergy and Infectious Diseases ranks it as a Category A Priority Pathogen and the
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georg ...
lists it as a Category A Bioterrorism Agent. It is also listed as a biological agent for export control by the Australia Group. 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 Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
, fever, and other symptoms similar to
Ebola 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 bec ...
, 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. In 2009, expanded
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s of an
Ebola 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 bec ...
and Marburg
vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. ...
began in
Kampala Kampala (, ) is the capital and largest city of Uganda. The city proper has a population of 1,680,000 and is divided into the five political divisions of Kampala Central Division, Kawempe Division, Makindye Division, Nakawa Division, and ...
, Uganda.


History


Discovery

Marburg virus was first described in 1967. It was discovered that year during a set of outbreaks of Marburg virus disease in the German cities of
Marburg Marburg ( or ) is a university town in the German federal state (''Bundesland'') of Hesse, capital of the Marburg-Biedenkopf district (''Landkreis''). The town area spreads along the valley of the river Lahn and has a population of approx ...
and
Frankfurt Frankfurt, officially Frankfurt am Main (; Hessian: , " Frank ford on the Main"), is the most populous city in the German state of Hesse. Its 791,000 inhabitants as of 2022 make it the fifth-most populous city in Germany. Located on its ...
and the Yugoslav capital Belgrade. Laboratory workers were exposed to tissues of infected
grivet monkey The grivet (''Chlorocebus aethiops'') is an Old World monkey with long white tufts of hair along the sides of its face. Some authorities consider this and all of the members of the genus ''Chlorocebus'' to be a single species, ''Cercopithecus ae ...
s (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.


Nomenclature

The virus is one of two members of the species ''
Marburg marburgvirus 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 primate ...
'', which is included in the genus ''
Marburgvirus 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 prim ...
'', family '' Filoviridae'', and order '' Mononegavirales''. The name Marburg virus is derived from
Marburg Marburg ( or ) is a university town in the German federal state (''Bundesland'') of Hesse, capital of the Marburg-Biedenkopf district (''Landkreis''). The town area spreads along the valley of the river Lahn and has a population of approx ...
(the city in
Hesse Hesse (, , ) or Hessia (, ; german: Hessen ), officially the State of Hessen (german: links=no, Land Hessen), is a state in Germany. Its capital city is Wiesbaden, and the largest urban area is Frankfurt. Two other major historic cities are Da ...
, Germany, where the virus was first discovered) and the taxonomic suffix ''virus''. Marburg virus was first introduced under this name in 1967. 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''. 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.


Virology


Genome

Like all mononegaviruses, marburgvirions contain non-infectious, linear nonsegmented, single-stranded
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
s of negative polarity that possess inverse-complementary 3' and 5' termini, do not possess a 5' cap, are not
polyadenylated Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...
, and are not covalently linked to a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
. Marburgvirus genomes are approximately 19 kbp long and contain seven
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s in the order
3'-UTR In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...
-''NP''-''VP35''-''VP40''-''GP''-''VP30''-''VP24''-''L''- 5'-UTR.


Structure

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. Marburgvirions are generally 80 nm in
width Length is a measure of distance. In the International System of Quantities, length is a quantity with dimension distance. In most systems of measurement a base unit for length is chosen, from which all other units are derived. In the Inter ...
, 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. Marburgvirions consist of seven structural proteins. At the center is the
helical Helical may refer to: * Helix A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is ...
ribonucleocapsid, which consists of the genomic RNA wrapped around a
polymer A polymer (; Greek ''poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic and ...
of nucleoproteins (NP). Associated with the ribonucleoprotein is the
RNA-dependent RNA polymerase RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to t ...
(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
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
ically distinct.


Entry

Niemann–Pick C1 (NPC1) cholesterol transporter protein appears to be essential for infection with both
Ebola 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 bec ...
and Marburg virus. Two independent studies reported in the same issue of ''
Nature Nature, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans ar ...
'' showed that
Ebola virus ''Zaire ebolavirus'', more commonly known as Ebola virus (; EBOV), 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 o ...
cell entry and replication requires NPC1. * * When cells from patients lacking NPC1 were exposed to Ebola virus in the laboratory, the cells survived and appeared immune to the
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
, 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. Furthermore, NPC1 was shown to be critical to
filovirus ''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 rela ...
entry because it mediates infection by binding directly to the
viral envelope A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. Numerous human pathogenic viruses in circulation are encase ...
glycoprotein and that the second lysosomal domain of NPC1 mediates this binding. In one of the original studies, a
small molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are ...
was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1. In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse-adapted Ebola virus.


Replication

The Marburg virus
life cycle Life cycle, life-cycle, or lifecycle may refer to: Science and academia * Biological life cycle, the sequence of life stages that an organism undergoes from birth to reproduction ending with the production of the offspring * Life-cycle hypothesi ...
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 The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
. The virus RdRp partially uncoats the nucleocapsid and transcribes the
genes In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
into positive-stranded
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
s, which are then translated into structural and nonstructural
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respondi ...
. 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. The most abundant protein produced is the nucleoprotein, whose
concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number 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 The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (the ...
. 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.


Ecology

In 2009, the successful isolation of infectious MARV was reported from caught healthy Egyptian fruit bats (''Rousettus aegyptiacus''). This isolation, together with the isolation of infectious RAVV, strongly suggests that
Old World The "Old World" is a term for Afro-Eurasia that originated in Europe , after Europeans became aware of the existence of the Americas. It is used to contrast the continents of Africa, Europe, and Asia, which were previously thought of by th ...
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. Experimentally infected bats developed relatively low viremia lasting at least 5 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.


Evolution

The viral strains fall into two clades: Ravn virus and Marburg virus. The Marburg strains can be divided into two: A and B. The A strains were isolated from
Uganda }), is a landlocked country in East Africa. The country is bordered to the east by Kenya, to the north by South Sudan, to the west by the Democratic Republic of the Congo, to the south-west by Rwanda, and to the south by Tanzania. The south ...
(five from 1967),
Kenya ) , national_anthem = " Ee Mungu Nguvu Yetu"() , image_map = , map_caption = , image_map2 = , capital = Nairobi , coordinates = , largest_city = Nairobi , ...
(1980) and
Angola , national_anthem = "Angola Avante"() , image_map = , map_caption = , capital = Luanda , religion = , religion_year = 2020 , religion_ref = , coordina ...
(2004–2005) while the B strains were from the
Democratic Republic of the Congo The Democratic Republic of the Congo (french: République démocratique du Congo (RDC), colloquially "La RDC" ), informally Congo-Kinshasa, DR Congo, the DRC, the DROC, or the Congo, and formerly and also colloquially Zaire, is a country in ...
epidemic (1999–2000) and a group of Ugandan isolates isolated in 2007–2009. 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.


Human disease

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
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
s diverge from the prototype Marburg marburgvirus or the Marburg virus variant Musoke (MARV/Mus) by <10% at the
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecul ...
level.


Recorded outbreaks


Prevention

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. 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. Of these models, the infection in macaques seems to be the most similar to the effects in humans. 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. 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. 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. 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. 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. 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.


Biological weapon

The
Soviet Union The Soviet Union,. officially the Union of Soviet Socialist Republics. (USSR),. was a List of former transcontinental countries#Since 1700, transcontinental country that spanned much of Eurasia from 1922 to 1991. A flagship communist state, ...
had an extensive offensive and defensive
biological weapon A biological agent (also called bio-agent, biological threat agent, biological warfare agent, biological weapon, or bioweapon) is a bacterium, virus, protozoan, parasite, fungus, or toxin that can be used purposefully as a weapon in bioterroris ...
s program that included MARV. 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 Sergiyev Posad ( rus, Се́ргиев Поса́д, p=ˈsʲɛrgʲɪ(j)ɪf pɐˈsat) is a city and the administrative center of Sergiyevo-Posadsky District in Moscow Oblast, Russia. Population: It was previously known as ''Sergiyev Posad'' (unt ...
), 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. As most performed research was highly
classified Classified may refer to: General *Classified information, material that a government body deems to be sensitive *Classified advertising or "classifieds" Music *Classified (rapper) (born 1977), Canadian rapper *The Classified, a 1980s American roc ...
, 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 ; kk, Қазақ Советтік Социалистік Республикасы) *1991: Republic of Kazakhstan (russian: Республика Казахстан; kk, Қазақстан Республикасы) , linking_name = the ...
(today
Kazakhstan Kazakhstan, officially the Republic of Kazakhstan, is a transcontinental country located mainly in Central Asia and partly in Eastern Europe. It borders Russia Russia (, , ), or the Russian Federation, is a transcontinental coun ...
), 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. MARV is a select agent under US law.


References


Further reading

* * * * *


External links


International Committee on Taxonomy of Viruses (ICTV)

FILOVIR—scientific resources for research on filoviruses
{{Taxonbar, from=Q6755280 Animal viral diseases Arthropod-borne viral fevers and viral haemorrhagic fevers Biological weapons Hemorrhagic fevers Tropical diseases Primate diseases Zoonoses Filoviridae Negative-sense single-stranded RNA viruses