Orthopox
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''Orthopoxvirus'' is a genus of
virus A virus is a 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 archaea. Viruses are ...
es in the family ''
Poxviridae ''Poxviridae'' is a family of double-stranded DNA viruses. Vertebrates and arthropods serve as natural hosts. The family contains 22 genera that are assigned to two subfamilies: ''Chordopoxvirinae'' and ''Entomopoxvirinae''. ''Entomopoxvirinae'' ...
'' and subfamily ''
Chordopoxvirinae ''Chordopoxvirinae'' is a subfamily of viruses in the Family (biology), family ''Poxviridae''. Vertebrate, Vertebrates and Arthropod, arthropods serve as natural hosts. The subfamily contains 18 Genus, genera. Diseases associated with this subfa ...
''. Vertebrates, including mammals and humans, and
arthropod Arthropods ( ) are invertebrates in the phylum Arthropoda. They possess an arthropod exoskeleton, exoskeleton with a cuticle made of chitin, often Mineralization (biology), mineralised with calcium carbonate, a body with differentiated (Metam ...
s serve as natural hosts. There are 12 species in this genus. Diseases associated with this genus include
smallpox Smallpox was an infectious disease caused by Variola virus (often called Smallpox virus), which belongs to the genus '' Orthopoxvirus''. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (W ...
,
cowpox Cowpox is an infectious disease caused by Cowpox virus (CPXV). It presents with large blisters in the skin, a fever and swollen glands, historically typically following contact with an infected cow, though in the last several decades more often ...
, horsepox, camelpox, and
mpox Mpox (, ; formerly known as monkeypox) is an infectious viral disease that can occur in humans and other animals. Symptoms include a rash that forms blisters and then crusts over, fever, and swollen lymph nodes. The illness is usually mild, ...
. The most widely known member of the genus is Variola virus, which causes smallpox. It was eradicated globally by 1977, through the use of
Vaccinia virus The vaccinia virus (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the ...
as a
vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifi ...
. The most recently described species is the Borealpox virus, first isolated in 2015.


Microbiology


Structure

Orthopoxviruses are enveloped with brick-shaped geometries and virion dimensions around 200 nm wide and 250 nm long.


Genome

Member viruses have linear double-stranded DNA genomes around 170–250 kb in length.


Lifecycle

Viral replication Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome ...
is cytoplasmic. Entry into the host cell is achieved by attachment of the viral proteins to host
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 a uronic sugar and an amino sugar, except in the case o ...
s (GAGs), which mediate cellular
endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
of the virus. Fusion of 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. A viral envelope protein or E protein is a protein in the en ...
with the plasma membrane releases the
viral core A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or ma ...
into the host
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
. Expression of early-phase genes by viral
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template. Using the e ...
begins at 30 minutes after infection. The viral core is completely uncoated as early expression ends, releasing the viral genome into the cytoplasm. At this point, intermediate genes are expressed, triggering genomic DNA replication by the viral
DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...
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 a spherical immature particle. This virus particle matures into the brick-shaped intracellular mature virion, which can be released upon cell
lysis Lysis ( ; from Greek 'loosening') is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ...
, or can acquire a second membrane from the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
and bud as extracellular enveloped virions. In this latter case, the virion is transported to the plasma membrane via
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
s.


Transmission

Natural hosts of orthopoxviruses are
mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
s and
arthropod Arthropods ( ) are invertebrates in the phylum Arthropoda. They possess an arthropod exoskeleton, exoskeleton with a cuticle made of chitin, often Mineralization (biology), mineralised with calcium carbonate, a body with differentiated (Metam ...
s. Member viruses are transmitted by respiratory droplets, contact, and
zoonosis A zoonosis (; plural zoonoses) or zoonotic disease is an infectious disease of humans caused by a pathogen (an infectious agent, such as a virus, bacterium, parasite, fungi, or prion) that can jump from a non-human vertebrate to a human. When ...
.


Distribution

Some orthopoxviruses, including 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 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.


Taxonomy

The genus contains the following species, listed by scientific name and followed by the exemplar virus of the species: * ''Orthopoxvirus abatinomacacapox'',
Orthopoxvirus Abatino ''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 wi ...
* ''Orthopoxvirus akhmetapox'', Akhmeta virus * ''Orthopoxvirus camelpox'', Camelpox virus * ''Orthopoxvirus cowpox'',
Cowpox virus Cowpox is an infectious disease caused by Cowpox virus (CPXV). It presents with large vesicle (dermatology), blisters in the skin, a fever and lymphadenopathy, swollen glands, historically typically following contact with an infected cow, though ...
* ''Orthopoxvirus ectromelia'', Ectromelia virus * ''Orthopoxvirus monkeypox'', Monkeypox virus * ''Orthopoxvirus raccoonpox'', Raccoonpox virus * ''Orthopoxvirus skunkpox'', Skunkpox virus * ''Orthopoxvirus taterapox'', Taterapox virus * ''Orthopoxvirus vaccinia'',
Vaccinia virus The vaccinia virus (VACV or VV) is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, which encodes approximately 250 genes. The dimensions of the ...
* ''Orthopoxvirus variola'', Variola virus * ''Orthopoxvirus volepox'', Volepox virus The related Borealpox virus, also known as Alaskapox virus, has not been classified as of 2024.


Evolution

Among the path of evolution of the ''Orthopoxvirus'' species, many genes are truncated (but still functional), fragmented, or lost. Cowpox strains tend to have the most intact genes. Predicting the
phylogeny A phylogenetic tree or phylogeny is a graphical representation which shows the evolutionary history between a set of species or Taxon, taxa during a specific time.Felsenstein J. (2004). ''Inferring Phylogenies'' Sinauer Associates: Sunderland, M ...
by sequence or by gene content produces somewhat different results: Some of the differences in the two trees are attributed to the procedure of passage in producing vaccinia strains. The
Modified vaccinia Ankara Modified vaccinia Ankara (MVA) is an attenuated (weakened) strain of the vaccinia virus. It is being used as a vaccine (called MVA-BN, brand names: Imvanex in the EU, Imvamune in Canada, and Jynneos in the US) against smallpox and mpox, having ...
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.


Infection in humans


Zoonoses

Following the eradication of the human-specific variola virus (smallpox), all human ''Orthopoxvirus'' infections are
zoonoses A zoonosis (; plural zoonoses) or zoonotic disease is an infectious disease of humans caused by a pathogen (an infectious agent, such as a virus, bacterium, parasite, fungi, or prion) that can jump from a non-human vertebrate to a human. When h ...
. Mpox occurs naturally only in Africa, particularly in the
Democratic Republic of the Congo The Democratic Republic of the Congo (DRC), also known as the DR Congo, Congo-Kinshasa, or simply the Congo (the last ambiguously also referring to the neighbouring Republic of the Congo), is a country in Central Africa. By land area, it is t ...
. However, human and
prairie dog Prairie dogs (genus ''Cynomys'') are herbivorous burrowing Marmotini, ground squirrels native to the grasslands of North America. There are five recognized species of prairie dog: black-tailed prairie dog, black-tailed, white-tailed prairie dog ...
cases have occurred in the US due to contact with animals imported from
Ghana Ghana, officially the Republic of Ghana, is a country in West Africa. It is situated along the Gulf of Guinea and the Atlantic Ocean to the south, and shares borders with Côte d’Ivoire to the west, Burkina Faso to the north, and Togo to t ...
, 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 The cat (''Felis catus''), also referred to as the domestic cat or house cat, is a small Domestication, domesticated carnivorous mammal. It is the only domesticated species of the family Felidae. Advances in archaeology and genetics have sh ...
, from which human infections are most often acquired. Cowpox virus has also infected a variety of animals in European zoos, such as
elephant Elephants are the largest living land animals. Three living species are currently recognised: the African bush elephant ('' Loxodonta africana''), the African forest elephant (''L. cyclotis''), and the Asian elephant ('' Elephas maximus ...
s, resulting in human infection.


Laboratory transmission

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 a lesser extent, farm workers.


Signs and symptoms

The initial symptoms of ''Orthopoxvirus'' infection include
fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
,
malaise In medicine, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. It is considered a vague termdescribing the state of simply not feeling well. The word has exist ...
, head and body aches, and occasionally
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
. With the exception of mpox infection, one lesion is the norm, although satellite lesions may be produced by accidental autoinoculation. Individual
lesions A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...
, surrounded by inflammatory tissue, develop and progress through
macules A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this sys ...
,
papules A papule is a small, well-defined bump in the skin. It may have a rounded, pointed or flat top, and may have a dip. It can appear with a stalk, be thread-like or look warty. It can be soft or firm and its surface may be rough or smooth. Some ...
, vesicles, and
pustules A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this sys ...
, and eventually become dry crusts. (Lesions alone are not diagnostic for ''Orthopoxvirus ''infection and may be mistaken for zoonotic ''
Parapoxvirus ''Parapoxvirus'' is a genus of viruses, in the family ''Poxviridae'', in the subfamily ''Chordopoxvirinae''. Like all members of the family Poxviridae, they are oval, relatively large, double-stranded DNA viruses. Parapoxviruses have a unique sp ...
'' infections,
anthrax Anthrax is an infection caused by the bacterium '' Bacillus anthracis'' or ''Bacillus cereus'' biovar ''anthracis''. Infection typically occurs by contact with the skin, inhalation, or intestinal absorption. Symptom onset occurs between one ...
or ''
Herpesvirus ''Orthoherpesviridae'', previously named and more widely known as ''Herpesviridae'', is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are commonly known as herp ...
'' infections.) With severe infections, severe
edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...
and
erythema Erythema (, ) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not associated with pathology inc ...
may affect large areas of the body.
Encephalitis Encephalitis is inflammation of the Human brain, brain. The severity can be variable with symptoms including reduction or alteration in consciousness, aphasia, headache, fever, confusion, a stiff neck, and vomiting. Complications may include se ...
(alteration of mental status and focal neurologic deficits),
myelitis Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord can cause the myelin and axon to be damaged re ...
(upper- and lower-motor
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
dysfunction, sensory level, and bowel and bladder dysfunction), or both may result from ''Orthopoxvirus'' infection. Rarely, orthopoxviruses may be detected in
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
. Regarding specific ''Orthopoxvirus'' infections, human mpox most resembles mild smallpox. Human cowpox is a relatively severe localized infection. A survey of 54 cases reported three cases of generalized infection, including one death.


Treatment

Vaccinia-specific
immunoglobulins An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that cause di ...
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 is effective for treatment of eczema vaccinatum and certain cases of progressive vaccinia. However, VIG is contraindicated for the treatment of vaccinial
keratitis Keratitis is a condition in which the human eye, eye's cornea, the clear dome on the front surface of the eye, becomes inflammation, inflamed. The condition is often marked by moderate to intense pain and usually involves any of the following sy ...
. 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 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 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 Tecovirimat, sold under the brand name Tpoxx among others, is an Antiviral drug, antiviral medication with activity against orthopoxviruses such as smallpox and monkeypox, mpox. In 2018 it was the first antipoxviral drug approved in the United S ...
(ST-246) have been reported to be 100% active against vaccinia virus or other orthopoxviruses ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' and among test animals. Tecovirimat has been granted orphan drug status by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) and is currently under study to determine its safety and effectiveness in humans. Another example is
brincidofovir Brincidofovir, sold under the brand name Tembexa, is an antiviral drug used to treat smallpox. Brincidofovir is a prodrug of cidofovir. Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher int ...
. 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 In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
. The decision followed a priority review by the agency, motivated by growing concern of potential
bioweapon Biological agents, also known as biological weapons or bioweapons, are pathogens used as weapons. In addition to these living or replicating pathogens, toxins and biotoxins are also included among the bio-agents. More than 1,200 different kin ...
development. Since 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 ''Cytomegalovirus'' (CMV) (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betaherp ...
infections in humans.
Imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases ...
, 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 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.


Lab synthesis

In the summer of 2017, researchers at the
University of Alberta The University of Alberta (also known as U of A or UAlberta, ) is a public research university located in Edmonton, Alberta, Canada. It was founded in 1908 by Alexander Cameron Rutherford, the first premier of Alberta, and Henry Marshall Tory, t ...
recreated horsepox via lab synthesis to conduct research into using viruses to treat cancer.


References


External links


Viralzone: Orthopoxvirus

ICTV

Virus Pathogen Database and Analysis Resource (ViPR): Poxviridae
{{Taxonbar, from=Q740335 Chordopoxvirinae Virus genera fr:Orthopoxvirus