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37-464: Vaccinia virus is member of Orthopoxvirus family. These viruses contain approximately 200 genes in their genome . About one third of the genome is not necessary for the viral replication itself. These viral products interfere with the host immune response . SPI-2 is one of these immunomodulatory factors. SPI-2 is a nonglycosylated peptide with size of 38,5 kDa. It is expressed in an early phase of infection . The initiation site for transcription

74-595: A uronic sugar and an amino sugar , except in the case of the sulfated glycosaminoglycan keratan , where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers. Mucopolysaccharidoses are a group of metabolic disorders in which abnormal accumulations of glycosaminoglycans occur due to enzyme deficiencies. Glycosaminoglycans vary greatly in molecular mass, disaccharide structure, and sulfation . This

111-652: A 2- O mannose. Elongation of the keratan sulfate polymer occurs through the glycosyltransferase addition of Gal and GlcNAc. Galactose addition occurs primarily through the β-1,4-galactosyltransferase enzyme (β4Gal-T1) while the enzymes responsible for β-3-Nacetylglucosamine have not been clearly identified. Finally, sulfation of the polymer occurs at the 6-position of both sugar residues. The enzyme KS-Gal6ST ( CHST1 ) transfers sulfate groups to galactose while N-acetylglucosaminyl-6-sulfotransferase (GlcNAc6ST) ( CHST2 ) transfers sulfate groups to terminal GlcNAc in keratan sulfate. The fourth class of GAG, hyaluronic acid (HA),

148-429: A 24- to 36-hour period. Doses can be repeated, usually at intervals of 2–3 days, until recovery begins (i.e., no new lesions appear). The CDC is currently the only source of VIG for civilians. Certain antiviral compounds such as tecovirimat (ST-246) have been reported to be 100% active against vaccinia virus or other orthopoxviruses in vitro and among test animals. Tecovirimat has been granted orphan drug status by

185-693: A lesser extent, farm workers. The initial symptoms of Orthopoxvirus infection include fever , malaise , head and body aches, and occasionally vomiting . With the exception of mpox infection, one lesion is the norm, although satellite lesions may be produced by accidental autoinoculation. Individual lesions , surrounded by inflammatory tissue, develop and progress through macules , papules , vesicles , and pustules , and eventually become dry crusts. (Lesions alone are not diagnostic for Orthopoxvirus infection and may be mistaken for zoonotic Parapoxvirus infections, anthrax or Herpesvirus infections. ) Severe edema and erythema may affect large areas of

222-657: A lethal challenge with vaccinia. Currently, imatinib and related compounds are being evaluated by the CDC for their efficacy against variola virus and mpox virus. In the summer of 2017, researchers at the University of Alberta recreated horsepox via lab synthesis to conduct research into using viruses to treat cancer . Glycosaminoglycan Glycosaminoglycans ( GAGs ) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of

259-638: A multimeric enzyme encoded by EXT1 and EXT2 of the EXT family of genes, transfers both GlcNAc and GlcA for HSGAG chain elongation. While elongating, the HSGAG is dynamically modified, first by N-deacetylase, N-sulfotransferase ( NDST1 ), which is a bifunctional enzyme that cleaves the N-acetyl group from GlcNAc and subsequently sulfates the N-position. Next, C-5 uronyl epimerase coverts d-GlcA to l-IdoA followed by 2- O sulfation of

296-575: A spherical immature particle. This virus particle matures into the brick-shaped intracellular mature virion, which can be released upon cell lysis , or can acquire a second membrane from the Golgi apparatus and bud as extracellular enveloped virions. In this latter case, the virion is transported to the plasma membrane via microtubules . Natural hosts of orthopoxviruses are mammals and arthropods . Member viruses are transmitted by respiratory droplets, contact, and zoonosis . Some orthopoxviruses, including

333-604: A variety of animals in European zoos, such as elephants , resulting in human infection. Aerosols of concentrated virus may result in Orthopoxvirus infection, especially in unimmunized individuals. In addition, needle sticks with concentrated virus or scratches from infected animals may result in local infection of the skin even in immunized individuals. Cowpox infection in Europe is an occupational hazard for veterinary workers, and to

370-476: Is a relatively severe localized infection. A survey of 54 cases reported three cases of generalized infection, including one death. Vaccinia-specific immunoglobulins may be administered to infected individuals. The only product currently available for treatment of complications of Orthopoxvirus infection is vaccinia immunoglobulin (VIG), which is an isotonic sterile solution of the immunoglobulin fraction of plasma from persons vaccinated with vaccinia virus. It

407-570: Is because GAG synthesis is not template driven, as are proteins or nucleic acids, but constantly altered by processing enzymes. GAGs are classified into four groups, based on their core disaccharide structures: HSGAG and CSGAG modified proteoglycans first begin with a consensus Ser-Gly/Ala-X-Gly motif in the core protein. Construction of a tetrasaccharide linker that consists of -GlcAβ1–3Galβ1–3Galβ1–4Xylβ1-O-(Ser)-, where xylosyltransferase , β4-galactosyl transferase (GalTI),β3-galactosyl transferase (GalT-II), and β3-GlcA transferase (GlcAT-I) transfer

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444-455: Is cytoplasmic. Entry into the host cell is achieved by attachment of the viral proteins to host glycosaminoglycans (GAGs), which mediate cellular endocytosis of the virus. Fusion of the viral envelope with the plasma membrane releases the viral core into the host cytoplasm . Expression of early-phase genes by viral RNA polymerase begins at 30 minutes after infection. The viral core is completely uncoated as early expression ends, releasing

481-453: Is effective for treatment of eczema vaccinatum and certain cases of progressive vaccinia. However, VIG is contraindicated for the treatment of vaccinial keratitis . VIG is recommended for severe generalized vaccinia if the patient is extremely ill or has a serious underlying disease. VIG provides no benefit in the treatment of postvaccinal encephalitis and has no role in the treatment of smallpox. Current supplies of VIG are limited, and its use

518-521: Is not sulfated and is synthesized by three transmembrane synthase proteins HAS1 , HAS2 , and HAS3 . HA, a linear polysaccharide, is composed of repeating disaccharide units of →4)GlcAβ(1→3)GlcNAcβ(1→ and has a very high molecular mass, ranging from 10 to 10 Da. Each HAS enzyme is capable of transglycosylation when supplied with UDP-GlcA and UDP-GlcNAc. HAS2 is responsible for very large hyaluronic acid polymers, while smaller sizes of HA are synthesized by HAS1 and HAS3. While each HAS isoform catalyzes

555-446: Is reserved for treatment of vaccine complications with serious clinical manifestations. The recommended dosage of the currently available VIG is 0.6 ml/kg of body weight. VIG must be administered intramuscularly and is ideally administered as early as possible after the onset of symptoms. Because therapeutic doses of VIG might be substantial (e.g., 42 ml for a person weighing 70 kg), the product may be administered in divided doses over

592-465: Is under normal circumstances activated by the formation of inflammasome . SPI-2 expression also inhibits the apoptotic pathway activated by Fas-ligand and TNFα . Deletion of SPI-2 leads to virus attenuation in vivo (observed in mice model after intranasal infection) but without any remarkable influence on the host immune response. That was one of the reasons this gene was targeted during search for more safe and efficient vaccine against smallpox . It

629-656: The Democratic Republic of the Congo . However, human and prairie dog cases have occurred in the US due to contact with animals imported from Ghana , while in May 2022 an outbreak of mpox began spreading globally. Cowpox only occurs in Europe and adjacent Russian states, and despite its name, occurs only rarely in cattle. One common host is the domestic cat , from which human infections are most often acquired. Cowpox virus has also infected

666-544: The Food and Drug Administration (FDA) and is currently under study to determine its safety and effectiveness in humans. Another example is brincidofovir . In June 2021, the FDA approved this drug for the treatment of smallpox in humans, making it the first drug approved for an effectively extinct mechanism of action . The decision followed a priority review by the agency, motivated by growing concern of potential bioweapon development. Since

703-444: The body in cases of severe infection. Encephalitis (alteration of mental status and focal neurologic deficits), myelitis (upper- and lower-motor neuron dysfunction, sensory level, and bowel and bladder dysfunction), or both may result from Orthopoxvirus infection. Rarely, orthopoxviruses may be detected in cerebrospinal fluid . Regarding specific Orthopoxvirus infections, human mpox most resembles mild smallpox. Human cowpox

740-824: The brain. CSGAGs interact with heparin binding proteins, specifically dermatan sulfate interactions with fibroblast growth factor FGF-2 and FGF-7 have been implicated in cellular proliferation and wound repair while interactions with hepatic growth factor/scatter factor (HGF/SF) activate the HGF/SF signaling pathway ( c-Met ) through its receptor. CSGAGs are important in providing support and adhesiveness in bone, skin, and cartilage. Other biological functions for which CSGAGs are known to play critical functions in include inhibition of axonal growth and regeneration in CNS development, roles in brain development, neuritogenic activity, and pathogen infection. Dermatan sulfates Dermatan sulfates function in

777-556: The consensus sequence NX(T/S) along with protein secondary structure was determined to be involved in N -linked oligosaccharide extension with keratan sulfate. Keratan sulfate elongation begins at the nonreducing ends of three linkage oligosaccharides, which define the three classes of keratan sulfate. Keratan sulfate I (KSI) is N -linked via a high mannose type precursor oligosaccharide. Keratan sulfate II (KSII) and keratan sulfate III (KSIII) are O -linked, with KSII linkages identical to that of mucin core structure, and KSIII linked to

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814-518: The differences in the two trees are attributed to the procedure of passage in producing vaccinia strains. The Modified vaccinia Ankara strain in this regard has much gene loss related to in vitro passage, and horsepox being a vaccinia strain found in a natural outbreak has less. Following the eradication of the human-specific variola virus (smallpox), all human Orthopoxvirus infections are zoonoses . Mpox occurs naturally only in Africa, particularly in

851-455: The enzyme that is utilized to build HSGAGs. EXTL2 and EXTL3, two genes in the EXT tumor suppressor family, have been shown to have GlcNAcT-I activity. Conversely, GalNAc is transferred to the linker by the enzyme GalNAcT to initiate synthesis of CSGAGs, an enzyme which may or may not have distinct activity compared to the GalNAc transferase activity of chondroitin synthase. With regard to HSGAGs,

888-504: The eradication of variola virus, camelpox has become one of the most economically important Orthopoxvirus infections, because many subsistence-level nomadic communities depend heavily on camels. The genus contains the following species: The related Borealpox virus , also known as Alaskapox virus, has not been classified as of 2024. Among the path of evolution of the Orthopoxvirus species, many genes are truncated (but still functional), fragmented, or lost. Cowpox strains tend to have

925-527: The four monosaccharides, begins synthesis of the GAG modified protein. The first modification of the tetrasaccharide linker determines whether the HSGAGs or CSGAGs will be added. Addition of a GlcNAc promotes the addition of HSGAGs while addition of GalNAc to the tetrasaccharide linker promotes CSGAG development. GlcNAcT-I transfers GlcNAc to the tetrasaccahride linker, which is distinct from glycosyltransferase GlcNAcT-II,

962-523: The genus is Variola virus , which causes smallpox. It was eradicated globally by 1977, through the use of Vaccinia virus as a vaccine . The most recently described species is the Borealpox virus , first isolated in 2015. Orthopoxviruses are enveloped with brick-shaped geometries and virion dimensions around 200 nm wide and 250 nm long. Member viruses have linear double-stranded DNA genomes around 170–250 kb in length. Viral replication

999-470: The host range and SPI-3 stops infected cells from fusing together. Orthopoxvirus See text Orthopoxvirus is a genus of viruses in the family Poxviridae and subfamily Chordopoxvirinae . Vertebrates, including mammals and humans, and arthropods serve as natural hosts. There are 12 species in this genus. Diseases associated with this genus include smallpox , cowpox , horsepox, camelpox , and mpox . The most widely known member of

1036-682: The most intact genes. Predicting the phylogeny by sequence or by gene content produces somewhat different results: Orthopoxvirus ectromelia Orthopoxvirus cowpox , Germany and Brighton Orthopoxvirus taterapox , Orthopoxvirus camelpox , Orthopoxvirus variola Orthopoxvirus monkeypox Orthopoxvirus cowpox , GRI strain Orthopoxvirus vaccinia , including rabbitpox and horsepox Orthopoxvirus ectromelia Orthopoxvirus cowpox Horsepox Orthopoxvirus vaccinia , including rabbitpox Orthopoxvirus variola Orthopoxvirus taterapox , Orthopoxvirus camelpox , Orthopoxvirus monkeypox Some of

1073-479: The mpox, cowpox, and buffalopox viruses, have the ability to infect non-reservoir species. Others, such as ectromelia and camelpox viruses, are highly host-specific. Vaccinia virus, maintained in vaccine institutes and research laboratories, has a very wide host range. Vaccine-derived vaccinia has been found replicating in the wild in Brazil, where it has caused infections in rodents, cattle, and even humans. Following

1110-476: The production of HSGAGs, C-5 uronyl epimerase converts d-GlcA to l-IdoA to synthesize dermatan sulfate. Three sulfation events of the CSGAG chains occur: 4- O and/or 6- O sulfation of GalNAc and 2- O sulfation of uronic acid. Four isoforms of the 4- O GalNAc sulfotransferases (C4ST-1, C4ST-2, C4ST-3, and D4ST-1) and three isoforms of the GalNAc 6- O sulfotransferases (C6ST, C6ST-2, and GalNAc4S-6ST) are responsible for

1147-410: The same biosynthetic reaction, each HAS isoform is independently active. HAS isoforms have also been shown to have differing K m values for UDP-GlcA and UDPGlcNAc. It is believed that through differences in enzyme activity and expression, the wide spectrum of biological functions mediated by HA can be regulated, such as its involvement with neural stem cell regulation in the subgranular zone of

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1184-486: The sulfation of GalNAc. Unlike HSGAGs and CSGAGs, the third class of GAGs, those belonging to keratan sulfate types, are driven towards biosynthesis through particular protein sequence motifs. For example, in the cornea and cartilage, the keratan sulfate domain of aggrecan consists of a series of tandemly repeated hexapeptides with a consensus sequence of E(E/L)PFPS. Additionally, for three other keratan sulfated proteoglycans, lumican , keratocan , and mimecan ( OGN ),

1221-456: The target virus is eradicated the efficacy could not be directly verified but was inferred via proxy, animal survival following infection by related species of Orthopoxvirus . In contrast, safety data was available from trials of the drug in treating Cytomegalovirus infections in humans. Imatinib , a compound approved by the FDA for cancer treatment, has been shown to limit the release of extracellular enveloped virions and to protect mice from

1258-414: The uronic acid sugar by 2- O sulfotransferase ( Heparan sulfate 2-O-sulfotransferase ). Finally, the 6- O and 3- O positions of GlcNAc moities are sulfated by 6- O ( Heparan sulfate 6-O-sulfotransferase ) and 3-O (3-OST) sulfotransferases. Chondroitin sulfate and dermatan sulfate, which comprise CSGAGs, are differentiated from each other by the presence of GlcA and IdoA epimers respectively. Similar to

1295-468: The viral genome into the cytoplasm. At this point, intermediate genes are expressed, triggering genomic DNA replication by the viral DNA polymerase about 100 minutes post-infection. Replication follows the DNA strand displacement model. Late genes are expressed from 140 min to 48 hours postinfection, producing all viral structural proteins. Assembly of progeny virions begins in cytoplasmic viral factories, producing

1332-862: Was identified about 72 nucleotides upstream from the open reading frame . The translated protein stays in the cytoplasm of the host cell. SPI-2 shares 92% of its amino acid sequence with the cowpox virus modifier of the cytokine response – known as crmA . SPI-2 belongs in superfamily of the inhibitors of serine proteases (serpins). Serpins are the most broadly distributed family of inhibitors of proteases . They were identified in all multicellular eukaryotic organisms . In mammals serpins are secreted in plasma where they serve as inhibitors of proteases involved in blood coagulation , inflammation and complement activation. SPI-2 inhibits processing of an inactive precursor of interleukin-1β (pro-IL-1β) to active form of this cytokine . It does so by binding to caspase 1 (or ICE – interleukin-1 converting enzyme) which

1369-455: Was shown that immunization with vaccinia virus with deleted SPI-2 and 1 and coexpressing IFNγ leads to strong attenuation but without decreasing host immune response. Host reaction was comparable to that on MVA virus (modified virus Ankara ) which serves as a smallpox vaccine nowadays. The Copenhagen strain of vaccinia virus only has a truncated version of this protein. Vaccinia virus encodes two more serpin - SPI-1 and SPI-3. SPI-1 influences

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