Pestivirus

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Pestivirus
pesttivaairs.png
Virions of Pestivirus sp.
Virus classification OOjs UI icon edit-ltr.svg
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Kitrinoviricota
Class: Flasuviricetes
Order: Amarillovirales
Family: Flaviviridae
Genus:Pestivirus
Species

Pestivirus is a genus of viruses, in the family Flaviviridae . Viruses in the genus Pestivirus infect mammals, including members of the family Bovidae (which includes cattle, sheep, and goats) and the family Suidae (which includes various species of swine). There are 11 species in this genus. Diseases associated with this genus include: hemorrhagic syndromes, abortion, and fatal mucosal disease. [1] [2]

Structure

Viruses in Pestivirus are enveloped, with spherical geometries. Their diameter is around 50 nm. Genomes are linear and not segmented, around 12kb in length. [1]

GenusStructureSymmetryCapsidGenomic arrangementGenomic segmentation
PestivirusIcosahedral-likePseudo T=3EnvelopedLinearMonopartite

Lifecycle

Entry into the host cell is achieved by attachment of the viral envelope protein E2 to host receptors, which mediates clathrin-mediated endocytosis. The main viral replication process happens in host cytoplasm. Replication follows the positive strand RNA virus replication model. An IRES RNA element at the 5'-nontranslated region (NTR) of the viral genome recruits viral and cellular translation factors to initiate viral protein translation. [3] Viral proteins are first translated as polyprotein, and then processed into individual structure and non-structure proteins by both viral and host proteases. [3] The virus exits the host cell by budding. Mammals serve as the natural hosts.When infected, the host sheds viruses in almost all body secretions including saliva, nasal discharge, milk, and faeces. [3] Vertical transmission (viruses crossing the placenta and infecting the fetus) are also common. [1]

GenusHost detailsTissue tropismEntry detailsRelease detailsReplication siteAssembly siteTransmission
PestivirusMammalsNoneClathrin-mediated endocytosisSecretionCytoplasmCytoplasmHorizontal and Vertical

Genome

Pestivirus viruses have a single strand of positive-sense RNA (i.e. RNA which can be directly translated into viral proteins) that is around 12.5 kilobases (kb) long (equal to the length of 12,500 nucleotides), but due to recombination events has been observed up to 16.5 kilobases in length. [4] Sometimes, virions (individual virus particles) contain sections of an animal's genome that have been duplicated, though this is not normally the case. Although lacking Poly-A tail at the 3' end of the genome, it contains stem-loop regions that might be involved in viral translation and replication. [5] The genome contains RNA to encode both structural and nonstructural proteins. The molecular biology of pestiviruses shares many similarities and peculiarities with the human hepaciviruses. Genome organisation and translation strategy are highly similar for the members of both genera. For BVDV, frequently nonhomologous RNA recombination events lead to the appearance of genetically distinct viruses that are lethal to the host. [6]

Transmission and prevention

Pestivirus A is widespread in Australia, mainly in cattle. Some adult cattle are immune to the disease, while others are lifelong carriers. If a foetus becomes infected within the first three to four months of gestation, then it will fail to develop antibodies towards the virus. In these cases, the animals often die before birth or shortly after. It is spread very easily among feedlot cattle as nasal secretions and close contact spread the disease, and animals with infected mucous membranes give off millions of particles of BVDV a day.[ citation needed ]

Symptoms of Pestivirus infection include diarrhoea, respiratory problems, and bleeding disorders.[ citation needed ]

Pestivirus A vaccines exist and the correct vaccine strain should be given, depending on the herd's location and the endemic strain in that region. This vaccination must be given regularly to maintain immunity.[ citation needed ]

Vaccines

There are 120 registered BVD vaccine products currently used around the world, mainly in North and South America. [7] These are conventional modified live virus (MLV) or inactivated/killed virus vaccines. [7] In pregnant animals live vaccines pose significant risk of vertical transmission of vaccine virus that can occasionally result in complications for calves. [8]  Most of the harm done by BVDV is to unborn calves and depends on the timing of infection. [9] Vaccination has not proved to be effective for Bovine Viral Diarrhea (BVD), as the presence of BVD has not lessened since the vaccine has been developed. [10] Animals who are affected by the virus during early fetal development may become persistently infected (PI) and lack an immune response to BVD. These animal’s presence in herds and them shedding virus can infect other animals in the herd before vaccination is possible. [11] PI animals do not produce antibodies and are the main source of infection for herds, so culling is necessary to eradicate infection sources. [3] Vaccines are not able to prevent fetal infections, so this poses a huge source of infection for cattle herds. [10]  Another reason for the inefficiency of the BVD vaccine is because of failure to vaccinate whole areas, rather than just individual herds. [11] Border Disease, which affects lambs, is also caused by Pestivirus, but has no vaccine at this time. [12]  Marker vaccines are beneficial tools for the eradication of animal diseases in regions with a high prevalence of the designated disease. The chimeric CP7_E2alf used to see how altered cell tropism affects pigs may not only serve as a tool for a better understanding of Pestivirus attachment, entry, and assembly, but also represent modified live CSFV "marker vaccines." [3]

Structural and non-structural proteins

Genomic RNA of pestiviruses is translated into a large polyprotein that is divided into several proteins. It has a single big open reading frame (ORF) that can encode roughly 4000 amino acids and a positive-sense ssRNA genome. Among the structural proteins that are N terminal in this polyprotein are three glycoproteins, which are referred to as E0, E1, and E2 depending on the order in which they end up appearing in the polyprotein. [13]  The nucleocapsid protein C and the three envelope glycoproteins Erns, E1, and E2 are the virion's structural components. [14] Beginning with a nascent cleavage between the precursor ErnsE1E2 and the capsid protein, glycoprotein processing is then carried out by cleavage at the C-terminal end of E2. [14] After being split into ErnsE1 and E2, ErnsE1 is then transformed into Erns and E1. A host signal peptidase located in the endoplasmic reticulum's lumen catalyzes the cleavage between Erns and E1, as well as that between E1 and E2 (ER). [15] A new type of signal peptidase cleavage site is identified in an RNA virus polyprotein. The most important structural protein is E2, which regulates cell tropism by interacting with cell surface receptors and inducing responses from cytotoxic T-lymphocytes and neutralizing antibodies. E2 is a type I transmembrane protein and has a mass of 55 kDa. All three glycoproteins aid in the attachment of the virus and its entry into target cells. Viral entry and contagiousness require heterodimeric E1-E2 molecules. E1 is categorized as a type I transmembrane protein and has a mass of 33 kDa. Of the three glycoproteins, the functions of E1 are the least developed and least understood. [16] A virus's glycoproteins must perform a variety of tasks throughout its life cycle in order for the virus to successfully infect cells or animals, multiply, and then leave the affected cells. These activities can be broken down into the three mutually exclusive categories of interacting with hosts to sustain itself throughout the animal population, interacting with cells to infect and replicate, and connecting with other viral proteins to form viable virions. Although it lacks a hydrophobic anchor sequence, the structural glycoprotein E(rns) of pestiviruses has been found to be connected to the virion and to membranes in infected cells via its COOH terminus. Erns, an envelope glycoprotein, was recently recognized as an RNase. RNases have a variety of biological effects. They have been proven to be immunosuppressive, neurotoxic, and antihelminthic. Erns severely reduced the protein synthesis of various kinds of lymphocytes without causing cell membrane damage. [17]  Symptoms of pestivirus infections include leukopenia and immunosuppression. In the pathogenesis of pestiviruses, ERNS is crucial. A pestivirus envelope glycoprotein called ERNS is crucial for virus attachment and cell infection. Erns lacks a transmembrane domain, unlike the other two envelope proteins E1 and E2, and a significant amount is secreted into the medium of infected. Erns's C-terminus serves as a membrane anchor, a retention/secretion signal, a binding site for cell surface glycosaminoglycans (GAGs), a signal peptidase cleavage site, and more. Erns has a mass of 44–48 kDa. [18] The protein is also present in some pure pestivirus virions, which begs the crucial and fascinating question of how it attaches to the pestivirus envelope. Virus-neutralizing antibodies primarily target the pestivirus E2 glycoproteins, which also function in receptor binding and host range limiting. At the moment where pestiviruses enter cells, their host specificity is probably influenced by the sequence and structure of E2. Enveloped viruses have created a variety of crafty invasion methods. [19]  For cell attachment and membrane fusion to occur, one or more viral envelope glycoproteins are required. In contrast to pestiviruses and hepacivirus, which both have two envelope glycoproteins, E1 and E2, members of the Flaviviridae family, such as flaviviruses, only have one glycoprotein, E, in their envelope. Although E2 participates in cell attachment, it is not yet known which protein causes membrane fusion. [20]

The bovine viral diarrhea virus (BVDV) is what causes bovine viral diarrhea (BVD). Bovine viral diarrhea virus type 1 (BVDV-1), Bovine viral diarrhea virus type 2 (BVDV-2), Border disease virus (BDV), and Classical swine fever (CSF) virus are the four recognized species in the genus Pestivirus of the family Flaviviridae. [21] Although progress has been made in recent decades in identifying the activities of the BVDV NSPs, research on the virus still mostly focuses on its structural protein. Understanding BVDV non-structural proteins would assist researchers to better comprehend viral replication and the molecular basis of viral persistent infection. Eight non-structural proteins (NSPs) are encoded by the bovine viral diarrhea virus (BVDV) (i.e., Npro, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). A single open reading frame is encoded by a singular, single-stranded, positive-stranded RNA of 12.3–16.5 kb in the BVDV (ORF). The coding sequence is NH2, and the ORF can be split into various parts to encode polyproteins. –Npro (p20) (p20) –C (p14) (p14) -Erns/E0(gp48), -E1(gp25), -E2(gp53), -p7, NS2(p54), -NS3(p80), -NS4A(p10), -NS4B(p30), -NS5A(p58), -NS5B(p75), -COOH. Individually or collectively, these proteins are involved in viral replication, transcription, and translation. Npro (p20), a protein specific to pestivirus with a molecular weight of roughly 20 kDa, is the first protein generated from the N-terminus of the viral polyprotein. BVDV Npro is a hydrophilic outer membrane protein that primarily consists of beta-sheets and random curling. [22] It lacks a signal peptide. Npro is also a self-protease that can catalyze the breakdown of developing polyproteins to create the BVDV C protein. Infected animals have innate immune suppression as a result of BVDV Npro's capacity to control the generation or inhibition of type I interferon (IFN-I) and alter the virus' ability to replicate.  A 6-7 kDa polypeptide generated from E2 called viral protein p7 has two domains. The other domain, which is present throughout infection in the cell as free p7 or E2-p7, is released by signal peptidase interpretation and is found at the C-terminus of E2 without being cleaved. However, because p7 was not found in BVDV particles, it was categorized as a non-structural protein. Although BVDV p7 can aid in the production of contagious BVDV particles and encourage virus release, the exact mechanisms behind these actions are still unknown. [23] With 450 amino acids, NS2 (p54) is a cysteine protease. A shared domain of the C-terminal protease structure and a hydrophobic N-terminal half-anchored protein membrane make up this structure. [24] NS2-NS3 cleavage is mediated by the self-protease in NS2, which may effectively cleave into NS2 and NS3 in the early stages of infection, and the degree of NS2-NS3 cleavage controls BVDV from RNA replication to morphological alterations. [25] Additionally, when the BVDV virus infects a cell, the cell chaperone DNAJC14 joins forces with the viral NS2-NS3 to facilitate the activation of the NS2 protease and the release of NS3, which facilitates the production of virions. [26] As a target antigen for ELISA BVDV detection, NS3 is a multifunctional protein with serine protease activity, helicase activity, and nucleoside triphosphatase (NTPase) activity. [13] Although it plays a significant role in the BVDV replicase and controls the viral RNAs ability to replicate, NS3 has little impact on the assembly of the virus. Only in the NS3/NS4A complex can the NS3 protease reach peak activity, after which the C-terminus of NS3 cleaves all downstream proteins. The replication of viral RNA will be hampered by the inactivation of the NS3 protease, helicase, and NTPase. Normal detection limits for the NS2-NS3 (p125) protein in Ncp and Cp BVDV-infected cells are 120 kDa. The cleavage of NS2-NS3 is connected to the replication of the virus in the early stages of virus infection. [13] A complex known as NS2-NS3/NS4A (NS2-3/4A) is created when NS4A joins with uncleaved NS2-NS3 (NS2-3) or NS3/NS4A. It can be utilized to support RNA replication and virus assembly as the fundamental element of virus particles. In the NS3/NS4A serine protease complex, NS4A functions as a protease cofactor, engaging with NS3 to catalyze the cleavage of downstream proteins NS4B, NS5A, and NS5B. [27] In particle assembly, NS2 and NS3 can replace uncut NS2-NS3 molecules, but the precise mechanism is still unknown. [13]  A 35 kDa hydrophobic protein with NTPase activity called NS4B (p30) is involved in the replication of the BVDV genome. [28] Due to interactions between the viral Npro, Erns, and NS4B and the host immune signaling pathways, BVDV can bypass the host immune response and cause persistent infection in cattle by blocking their innate immune responses. [29] The primary target for the diagnosis of diseases, the creation of vaccines, and the management of infections is NS4B. After viral infection, NS4B can trigger humoral and cellular immune responses thanks to its highly conserved epitopes. NS5B (p75), which features a functional motif typical of viral RNA-dependent RNA polymerase, is roughly 77 kDa in size (RdRp). It primarily participates in the process of virus-infected cell membrane rearrangement and catalyzes the creation of viral RNA. [30] The C-terminus of the BVDV polyprotein is where the NS5A (p58) and NS5B (p75) are separated. Infected cells typically contain NS5A (p58) as a single protein or as an uncleaved NS5A-NS5B complex. A hydrophilic, phosphorylated protein with a molecular weight of 58 kDa called NS5A is a part of the viral replicase. [31] Although NS5B has a significant impact on RNA replication, its lack of specificity may have an impact on the design of viral replicase. [32] A number of issues, including the pathogenic mechanism, the regulation of virus replication, and the interaction between p7, NS4B, NS5A, and other NSP, remain unresolved. [33]

Species

See also

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).

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

The hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.

<i>Dengue virus</i> Species of virus

Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. Four serotypes of the virus have been found, and a reported fifth has yet to be confirmed, all of which can cause the full spectrum of disease. Nevertheless, scientists' understanding of dengue virus may be simplistic as, rather than distinct antigenic groups, a continuum appears to exist. This same study identified 47 strains of dengue virus. Additionally, coinfection with and lack of rapid tests for Zika virus and chikungunya complicate matters in real-world infections.

<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>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>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>Murine coronavirus</i> Species of virus

Murine coronavirus (M-CoV) is a virus in the genus Betacoronavirus that infects mice. Belonging to the subgenus Embecovirus, murine coronavirus strains are enterotropic or polytropic. Enterotropic strains include mouse hepatitis virus (MHV) strains D, Y, RI, and DVIM, whereas polytropic strains, such as JHM and A59, primarily cause hepatitis, enteritis, and encephalitis. Murine coronavirus is an important pathogen in the laboratory mouse and the laboratory rat. It is the most studied coronavirus in animals other than humans, and has been used as an animal disease model for many virological and clinical studies.

<span class="mw-page-title-main">Bovine viral diarrhea</span> Significant economic disease of cattle caused by two species of Pestivirus

Bovine viral diarrhea (BVD), bovine viral diarrhoea or mucosal disease, previously referred to as bovine virus diarrhea (BVD), is an economically significant disease of cattle that is found in the majority of countries throughout the world. Worldwide reviews of the economically assessed production losses and intervention programs incurred by BVD infection have been published. The causative agent, bovine viral diarrhea virus (BVDV), is a member of the genus Pestivirus of the family Flaviviridae.

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<span class="mw-page-title-main">Hepatitis C virus nonstructural protein 5A</span>

Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without trans-membrane helices.

Flavivirin is an enzyme.

Pestivirus NS3 polyprotein peptidase is an enzyme. This enzyme catalyses the following chemical reaction

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

<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.

HPgV-2 is the second human pegivirus discovered. It was first identified in 2005 in blood of transfusion recipients and initially named hepegivirus 1 because it shared some genetic features with both pegiviruses and hepaciviruses. HPgV-2 was later independently discovered by another group in the blood of a HCV-infected patient who had undergone multiple blood transfusions and died from sepsis of unclear etiology. It was then named human pegivirus 2. HPgV-2 is now classified in the pegivirus genus as part of Pegivirus H species.

Border disease (BD) is a viral disease of sheep and goats, primarily causing congenital diseases, but can also cause acute and persistent infections. It first appeared in the border regions of England and Wales in 1959, and has since spread world-wide. Lambs that are born with BD are commonly known as 'hairy shakers' due to the primary presentation of the disease. The disease was recognized before the virus, therefore the common name of the disease predates the understanding of the viral pathology. The virus can cause a significant reduction in the percentage of surviving lambs, thus it has a large economic impact on farmers.

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.

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