Middelburg virus

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Middelburg virus
Alphavirus.png
Image of an Alphavirus Viral Structure. This exhibits the characteristic T=4 that MIDV also displays.
Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Kitrinoviricota
Class: Alsuviricetes
Order: Martellivirales
Family: Togaviridae
Genus: Alphavirus
Species:
Middelburg virus

Middelburg virus (MIDV) is an alphavirus of the Old World Group that has likely endemic and zoonotic potential. [1] It is of the viral family Togaviridae . It was isolated from mosquitos in 1957 in South Africa, MDIV antigens have now been found in livestock, horses, and humans. [1]

Contents

Image of a horse that could possibly be affected by MIDV. Horse in field.jpg
Image of a horse that could possibly be affected by MIDV.

Symptoms

Typical symptoms of MIDV include: fever, swollen/aching limbs, hyperactivity, and depression. [1] There is research suggesting that MIDV might cause neurologic disease. Some signs of the neurologic disease are: ataxia, paresis, seizures, and paralysis. [1] In these cases where MIDV infection led to neurologic disease, moderate meningoencephalitis was observed microscopically. [1] There have also been rare cases in horses where MIDV infection has led to jaundice, laminitic stance, and aborted pregnancy. [1]

Virus structure

Middelburg virus is a single stranded, linearly arranged, positive stranded RNA virus. MIDV has an enveloped capsid that contains an icosahedron structure. The icosahedron has a triangulation number (T) of 4, meaning it contains 240 monomers. It is thought to be part of the Semliki Forest clade of Alphaviridae [2]

Genome

A complete genomic sequence was made of the originally isolated MIDV-857 strand using a RT-qPCR method. [3] Researchers found that the genome was 11,674 nucleotides long, not including the 5'-terminal cap or polyA-tail. [3] They found that the 5'-terminal cap and polyA-tail fell between 180-220 residues. [3] Through this sequencing, it was determined that MIDV has a similar structure and organization of its genome in comparison to other alphaviruses. [3] MIDV possesses the same read-through stop codon between the genes nsP3 and nsP4, which is distinctive of alphaviruses. [3] This same study found that the MIDV E1 gene was likely formed through recombination with Semliki Forest virus, or a virus very similar to SFV. [3] The E1 gene is a membrane fusion protein that is important in viral entry and release. [4] Together, E1 and E2 are the glycoproteins that make up the Alphavirus envelope over the nucleocapsid. [4] A final finding of this study located a 112 nucleotide duplication in the 3' untranslated region (UTR) of the MIDV genome, implying that this virus is prone to duplication mutations. [3] In a similar study, MIDV was found to have two open reading frames (ORFs). [5] The first ORF encodes for nonstructural proteins, while the second ORF encodes the structural proteins like E1 and E2. [5] It is important to know the sequencing to understand if certain strains act differently by causing different symptoms (i.e. only arthritis, only encephalitis, or both). [6]

Replication cycle

Entry

Alphaviruses, like MIDV, use receptor-mediated endocytic uptake to get into a host cell. [4] Since no MIDV-specific cell entry literature could be found, the Alphavirus entry information that MIDV utilizes will be stated here. After being taken in through endocytosis, a low pH triggers a membrane fusion, which delivers the viral RNA genomes into the cell's cytoplasm. [4] It is not yet know which surface molecule acts as an Alphavirus receptor, but research is looking at cell surface heparan sulfate (HS) as a viable receptor considering its close relation to the E2 protein found on the Alphavirus envelope. [4] Research is also looking at DC-SIGN/L-SIGN as a receptor since it binds to mannose-rich carbohydrates that are often found in mosquitos, the vectors for Alphaviruses and MIDV. [4] Alphaviruses utilize the clathrin-mediated endocytic pathway. [4] Since presence of the Alphavirus does not have an effect on the number of clathrin-coated vesicles, it is assumed that the alphavirus takes advantage of the cells own processes without alteration. [6] Research has found that this endocytic uptake of alphaviruses can be stopped through injection of anti-clathrin drugs - this could be utilized in the future to make a vaccine. [4] After endocytic uptake, the virus is quickly delivered to the early endosome compartment, where a low pH then lyses the endosome and virus, exposing the cytoplasm to viral nucleocapsid. [4] Cholesterol is also necessary for the Alphavirus to undergo fusion. [7] This fusion of the endosomal membrane to the viral envelope allows the release of nucleocapsid into the cytoplasm of the host cell. [7] Almost immediately the nucleocapsid is uncoated, exposing the viral RNA to the host cytoplasm [7]

Replication and transcription

MIDV is a member of the family Togoviridae, which is hypothesized to use a "factory" replication process. [8] The "factories" in this case, are the host cell's endosomes and lysosomes. [8] The role of the endosome was explained above in the section on viral entry. The modified cellular lysosome creates a new vesicular structure termed the "cytopathic vacuole" (CPV) which can serve as a site for viral replication and possible transcription. [8] The relationship between the CPV and RER are believed to create a viable site for translation of structural proteins and assembly of nucleocapsids of newly synthesized viruses. [8] In replication, the (+)ssRNA genome is translated to make a polyprotein, which is in turn cleaved into the smaller structural proteins that are used in the replication and transcription of RNA. [9] From the viral RNA, a double-stranded RNA (dsRNA) template is made. [9] This dsRNA template then is transcribed and replicated, which is the new mRNA that is utilized for subsequent virus generations. [9]

Assembly and release

The subgenomic RNA (sgRNA) that was made prior to this begins the next step in the life cycle of MIDV: assembly and release. [9] The sgRNA codes for the structural proteins that will form the new virus. [9] The assembly of the new viral capsid occurs in the cytoplasm. [9] Finally, this newly synthesized capsid is enveloped by budding, a process that occurs when the virus exits the cells and is surrounded by the plasma membrane [9]

Possible Vectors

MIDV was first isolated from the mosquito species Ochlerotatus (Aedes) caballus, since then it has been found in other mosquito species in South Africa including: Aedes leneatopennis and Aedes albothorax . [2] The virus is limited to Africa, but due to the wide range of these mosquito hosts and possible travelling of horses and livestock, there is cause to believe it might spread elsewhere. [6] Sindbis virus, an extremely similar virus to MIDV has spread outside of Africa and effects humans. [6] The horses themselves cannot act as vectors to spread MIDV since the concentration of virus in the host blood stream is too small to infect a mosquito. [6]

Other host species include Ovis aries , Mansonia , and Aedes vittatus . [10]

Associated Disease

MIDV is classified as an Old World Alphavirus which also includes Semliki Forest virus (SFV), Ndumu virus, Barmah Forest virus, and the very well-known Chikungunya virus. [1] These diseases all have similar symptoms: arthritis, fever, and rash. [1] Current research is also pointing to Old World Alphaviruses leading to neurologic disease like their New World counterparts . [2] [6]

There is a similar group of Alphavirus known as the New World Alphaviruses that also share much in common with MIDV. These include: Eastern equine encephalitis (EEE) virus, and Venezuelan equine encephalitis virus. [1] These viruses are more notoriously associated with neurologic disease and are more likely to effect humans. [1]

Tropism

There is no literature on MIDV tropism; based on the symptoms, it can be deduced that the virus mostly affects host connective tissue at the joints, causing arthritis. [11] The virus also affects epithelial tissue in the form of a rash and nervous tissue in the form of encephalitis. [11]

Treatment

There is no known treatment for MIDV in horses currently. [6] Veterinarians may give anti-inflammatory drugs to affected animals to lessen the inflammatory response of the infection. [6] Horse owners can also take preemptive measure by using long-lasting repellants and mosquito netting. [6]

Related Research Articles

<i>Flaviviridae</i> Family of viruses

Flaviviridae is a family of enveloped positive-strand RNA viruses which mainly infect mammals and birds. They are primarily spread through arthropod vectors. The family gets its name from the yellow fever virus; flavus is Latin for "yellow", and yellow fever in turn was named because of its propensity to cause jaundice in victims. There are 89 species in the family divided among four genera. Diseases associated with the group include: hepatitis (hepaciviruses), hemorrhagic syndromes, fatal mucosal disease (pestiviruses), hemorrhagic fever, encephalitis, and the birth defect microcephaly (flaviviruses).

<i>Flavivirus</i> Genus of viruses

Flavivirus, renamed Orthoflavivirus in 2023, is a genus of positive-strand RNA viruses in the family Flaviviridae. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus and several other viruses which may cause encephalitis, as well as insect-specific flaviviruses (ISFs) such as cell fusing agent virus (CFAV), Palm Creek virus (PCV), and Parramatta River virus (PaRV). While dual-host flaviviruses can infect vertebrates as well as arthropods, insect-specific flaviviruses are restricted to their competent arthropods. The means by which flaviviruses establish persistent infection in their competent vectors and cause disease in humans depends upon several virus-host interactions, including the intricate interplay between flavivirus-encoded immune antagonists and the host antiviral innate immune effector molecules.

<span class="mw-page-title-main">Rubella virus</span> Species of virus

Rubella virus (RuV) is the pathogenic agent of the disease rubella, transmitted only between humans via the respiratory route, and is the main cause of congenital rubella syndrome when infection occurs during the first weeks of pregnancy.

<i>Lassa mammarenavirus</i> Type of viral hemorrhagic fever

Lassa mammarenavirus (LASV) is an arenavirus that causes Lassa hemorrhagic fever, a type of viral hemorrhagic fever (VHF), in humans and other primates. Lassa mammarenavirus is an emerging virus and a select agent, requiring Biosafety Level 4-equivalent containment. It is endemic in West African countries, especially Sierra Leone, the Republic of Guinea, Nigeria, and Liberia, where the annual incidence of infection is between 300,000 and 500,000 cases, resulting in 5,000 deaths per year.

<i>Tick-borne encephalitis virus</i> Species of virus

Tick-borne encephalitis virus (TBEV) is a positive-strand RNA virus associated with tick-borne encephalitis in the genus Flavivirus.

<i>Semliki Forest virus</i> Species of virus

The Semliki Forest virus is an alphavirus found in central, eastern, and southern Africa. It was first isolated from mosquitoes in the Semliki Forest, Uganda by the Uganda Virus Research Institute in 1942 and described by Smithburn and Haddow. It is known to cause disease in animals including humans.

<i>Mardivirus</i> Genus of viruses in the family Herpesviridae affecting Chickens, turkeys, and quail

Mardivirus is a genus of viruses in the order Herpesvirales, in the family Herpesviridae, in the subfamily Alphaherpesvirinae. Chickens, turkeys, and quail serve as natural hosts. There are six species in this genus. Diseases associated with this genus include: Marek's disease, which causes asymmetric paralysis of one or more limbs, neurological symptoms, and development of multiple lymphomas that manifest as solid tumors. Gallid herpesvirus 2 is the only one of these viruses known to be pathogenic and due to the antigenic similarity between the three viruses the other two have been used to vaccinate against Marek's disease. These viruses have double stranded DNA genomes with no RNA intermediate.

<i>Alphavirus</i> Genus of viruses

Alphavirus is a genus of RNA viruses, the sole genus in the Togaviridae family. Alphaviruses belong to group IV of the Baltimore classification of viruses, with a positive-sense, single-stranded RNA genome. There are 32 alphaviruses, which infect various vertebrates such as humans, rodents, fish, birds, and larger mammals such as horses, as well as invertebrates. Alphaviruses that could infect both vertebrates and arthropods are referred dual-host alphaviruses, while insect-specific alphaviruses such as Eilat virus and Yada yada virus are restricted to their competent arthropod vector. Transmission between species and individuals occurs mainly via mosquitoes, making the alphaviruses a member of the collection of arboviruses – or arthropod-borne viruses. Alphavirus particles are enveloped, have a 70 nm diameter, tend to be spherical, and have a 40 nm isometric nucleocapsid.

<i>Orthobunyavirus</i> Genus of viruses

Orthobunyavirus is a genus of the Peribunyaviridae family in the order Bunyavirales. There are currently ~170 viruses recognised in this genus. These have been assembled into 103 species and 20 serogroups.

Mayaro virus disease is a mosquito-borne zoonotic pathogen endemic to certain humid forests of tropical South America. Infection with Mayaro virus causes an acute, self-limited dengue-like illness of 3–5 days' duration. The causative virus, abbreviated MAYV, is in the family Togaviridae, and genus Alphavirus. It is closely related to other alphaviruses that produce a dengue-like illness accompanied by long-lasting arthralgia. It is only known to circulate in tropical South America.

Batai orthobunyavirus (BATV) is a RNA virus belonging to order Bunyavirales, genus Orthobunyavirus.

Entebbe bat virus is an infectious disease caused by a Flavivirus that is closely related to yellow fever.

<i>Eilat virus</i> Species of virus

Eilat virus (EILV) is a unique Alphavirus which is known mainly for its host range restriction generally to insects by means of RNA replication. The virus is found in the Negev desert. It is incapable of infecting vertebrate cells, differentiating it from other alphaviruses.

<i>West Nile virus</i> Species of flavivirus causing West Nile fever

West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family Flaviviridae, from the genus Flavivirus, which also contains the Zika virus, dengue virus, and yellow fever virus. The virus is primarily transmitted by mosquitoes, mostly species of Culex. The primary hosts of WNV are birds, so that the virus remains within a "bird–mosquito–bird" transmission cycle. The virus is genetically related to the Japanese encephalitis family of viruses. Humans and horses both exhibit disease symptoms from the virus, and symptoms rarely occur in other animals.

<i>Pneumoviridae</i> Family of viruses

Pneumoviridae is a family of negative-strand RNA viruses in the order Mononegavirales. Humans, cattle, and rodents serve as natural hosts. Respiratory tract infections are associated with member viruses such as human respiratory syncytial virus. There are five species in the family which are divided between the genera Metapneumovirus and Orthopneumovirus. The family used to be considered as a sub-family of Paramyxoviridae, but has been reclassified as of 2016.

Mammalian orthoreovirus (MRV) is a double-stranded RNA virus. It is a part of the family Reoviridae, as well as the subfamily Spinareovirinae. As seen in the name, the Mammalian Ortheoreovirus infects numerous mammalian species and vertebrates which serve as natural hosts. Some diseases that occur as a result of this virus or are associated with this virus include mild upper respiratory illness, and gastrointestinal illness. Examples of these are: upper respiratory tract syndromes, gastroenteritis, biliary atresia, obstructive hydrocephalus, jaundice, alopecia, conjunctivitis, and ‘oily hair’ associated with steatorrhea.

Yokose virus (YOKV) is in the genus Flavivirus of the family Flaviviridae. Flaviviridae are often found in arthropods, such as mosquitoes and ticks, and may also infect humans. The genus Flavivirus includes over 50 known viruses, including Yellow Fever, West Nile Virus, Zika Virus, and Japanese Encephalitis. Yokose virus is a new member of the Flavivirus family that has only been identified in a few bat species. Bats have been associated with several emerging zoonotic diseases such as Ebola and SARS.

<i>Sepik virus</i> Mosquito transmitted virus endemic to Papua New Guinea

Sepik virus (SEPV) is an arthropod-borne virus (arbovirus) of the genus Flavivirus and family Flaviviridae. Flaviviridae is one of the most well characterized viral families, as it contains many well-known viruses that cause diseases that have become very prevalent in the world, like Dengue virus. The genus Flavivirus is one of the largest viral genera and encompasses over 50 viral species, including tick and mosquito borne viruses like Yellow fever virus and West Nile virus. Sepik virus is much less well known and has not been as well-classified as other viruses because it has not been known of for very long. Sepik virus was first isolated in 1966 from the mosquito Mansoniaseptempunctata, and it derives its name from the Sepik River area in Papua New Guinea, where it was first found. The geographic range of Sepik virus is limited to Papua New Guinea, due to its isolation.

<i>Modoc virus</i> Species of virus

Modoc virus (MODV) is a rodent-associated flavivirus. Small and enveloped, MODV contains positive single-stranded RNA. Taxonomically, MODV is part of the Flavivirus genus and Flaviviridae family. The Flavivirus genus includes nearly 80 viruses, both vector-borne and no known vector (NKV) species. Known flavivirus vector-borne viruses include Dengue virus, Yellow Fever virus, tick-borne encephalitis virus, and West Nile virus.

Rio Negro virus is an alphavirus that was first isolated in Argentina in 1980. The virus was first called Ag80-663 but was renamed to Rio Negro virus in 2005. It is a former member of the Venezuelan equine encephalitis complex (VEEC), which are a group of alphaviruses in the Americas that have the potential to emerge and cause disease. Río Negro virus was recently reclassified as a distinct species. Closely related viruses include Mucambo virus and Everglades virus.

References

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