Bovine papillomavirus
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Bovine papillomaviruses (BPV) are a
paraphyletic In taxonomy (general), taxonomy, a group is paraphyletic if it consists of the group's most recent common ancestor, last common ancestor and most of its descendants, excluding a few Monophyly, monophyletic subgroups. The group is said to be pa ...
group of
DNA virus A DNA virus is a virus that has a genome made of deoxyribonucleic acid (DNA) that is replicated by a DNA polymerase. They can be divided between those that have two strands of DNA in their genome, called double-stranded DNA (dsDNA) viruses, and ...
es of the subfamily '' Firstpapillomavirinae'' of ''
Papillomaviridae ''Papillomaviridae'' is a family of non- enveloped DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected ...
'' that are common in
cattle Cattle (''Bos taurus'') are large, domesticated, cloven-hooved, herbivores. They are a prominent modern member of the subfamily Bovinae and the most widespread species of the genus ''Bos''. Adult females are referred to as cows and adult mal ...
. All BPVs have a
circular Circular may refer to: * The shape of a circle * ''Circular'' (album), a 2006 album by Spanish singer Vega * Circular letter (disambiguation) ** Flyer (pamphlet), a form of advertisement * Circular reasoning, a type of logical fallacy * Circula ...
double-stranded DNA genome. Infection causes
wart Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...
s (
papilloma A papilloma (plural papillomas or papillomata) ('' papillo-'' + '' -oma'') is a benign epithelial tumor growing exophytically (outwardly projecting) in nipple-like and often finger-like fronds. In this context, papilla refers to the projection cre ...
s and fibropapillomas) of the
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
and
alimentary tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
, and more rarely cancers of the alimentary tract and
urinary bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...
. They are also thought to cause the skin tumour
equine sarcoid Skin cancer, or neoplasia, is the most common type of cancer diagnosed in horses, accounting for 45Beuchner-Maxwell, "Skin tumors.", pg. 692 to 80% of all cancers diagnosed. Sarcoids are the most common type of skin neoplasm and are the most common ...
in
horse The horse (''Equus ferus caballus'') is a domesticated, one-toed, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two extant subspecies of ''Equus ferus''. The horse has evolved over the past 45 to 55 million y ...
s and
donkey The domestic donkey is a hoofed mammal in the family Equidae, the same family as the horse. It derives from the African wild ass, ''Equus africanus'', and may be classified either as a subspecies thereof, ''Equus africanus asinus'', or as a ...
s. BPVs have been used as a model for studying papillomavirus molecular biology and for dissecting the mechanisms by which this group of viruses cause
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
.


Structure and genetic organisation

Like other papillomaviruses, BPVs are small non-enveloped viruses with an
icosahedral In geometry, an icosahedron ( or ) is a polyhedron with 20 faces. The name comes and . The plural can be either "icosahedra" () or "icosahedrons". There are infinitely many non- similar shapes of icosahedra, some of them being more symmetrica ...
capsid around 50–60 nm in diameter. The capsid is formed of the L1 and L2 structural proteins, with the L1
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
exposed. All BPVs have a
circular Circular may refer to: * The shape of a circle * ''Circular'' (album), a 2006 album by Spanish singer Vega * Circular letter (disambiguation) ** Flyer (pamphlet), a form of advertisement * Circular reasoning, a type of logical fallacy * Circula ...
double-stranded DNA genome of 7.3–8.0 kb. The genetic organisation of those BPVs which have been sequenced is broadly similar to other papillomaviruses. The
open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...
s (ORFs) are all located on one strand, and are divided into early and late regions. The early region encodes nonstructural proteins E1 to E7. There are three viral oncoproteins, E5, E6 and E7; BPVs of the ''Xipapillomavirus'' group lack E6. The late region encodes structural proteins L1 and L2. There is also a non-coding long control region (LCR).


Types

Six types of BPV have been characterised, BPV-1 to BPV-6, which are divided into three broad subgroups. * '' Deltapapillomavirus'' or fibropapillomaviruses (formerly known as subgroup A), including types 1 and 2, have a genome of around 7.9 kb. Similar papillomaviruses of
ungulate Ungulates ( ) are members of the diverse clade Ungulata which primarily consists of large mammals with hooves. These include odd-toed ungulates such as horses, rhinoceroses, and tapirs; and even-toed ungulates such as cattle, pigs, giraffes, cam ...
s (e.g.
deer papillomavirus Deer or true deer are hoofed ruminant mammals forming the family Cervidae. The two main groups of deer are the Cervinae, including the muntjac, the elk (wapiti), the red deer, and the fallow deer; and the Capreolinae, including the reindeer ...
,
European elk papillomavirus European, or Europeans, or Europeneans, may refer to: In general * ''European'', an adjective referring to something of, from, or related to Europe ** Ethnic groups in Europe ** Demographics of Europe ** European cuisine, the cuisines of Europe a ...
,
ovine papillomavirus Sheep or domestic sheep (''Ovis aries'') are domesticated, ruminant mammals typically kept as livestock. Although the term ''sheep'' can apply to other species in the genus ''Ovis'', in everyday usage it almost always refers to domesticated sh ...
1,2) are also found in this group. Like all members of the papillomavirus class, these viruses infect only
keratinocytes Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referred ...
(epithelial cells); however, unlike other papillomaviruses, they cause proliferation of both keratinocytes and
fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s, causing benign fibropapillomas involving both the
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
and the underlying
dermis The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided i ...
. The specificity of the types differs: ** BPV-1 infects paragenital areas, including penis, teats and udders ** BPV-2 infects skin, alimentary canal and urinary bladder * '' Xipapillomavirus'' or epitheliotropic BPVs (formerly known as subgroup B), including types 3, 4 and 6, have a smaller genome of around 7.3 kb and are unique among papillomaviruses in lacking the E6 oncoprotein. They infect keratinocytes (epithelial cells), causing pure papillomas involving only the
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
. The specificity of the types differs: ** BPV-3 infects skin ** BPV-4 infects the upper alimentary tract ** BPV-6 infects teats and udders * ''
Epsilonpapillomavirus ''Epsilonpapillomavirus'' is a genus of viruses, in the family ''Papillomaviridae''. Cattle serve as natural hosts and it is one of the bovine papillomaviruses. There are two species in this genus. Diseases associated with this genus include: fi ...
'' has the single member BPV-5, with features intermediate between the other two groups. BPV-5 infects teats and udders, and can cause both pure papillomas and fibropapillomas. A further thirteen putative BPVs have recently been identified; the novel viruses have yet to be assigned to subgroups.


Pathology

BPV is highly prevalent, with around 50% of cattle being estimated to bear lesions in the UK. Cutaneous warts are most common in younger animals (under 2 years) and usually spontaneously regress due to the animal's
immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
without significant scarring. The duration of infection is very variable (from one month to over a year) and recurrence is possible. Warts caused by the ''Xipapillomavirus'' group have a cauliflower-like appearance and can attain the size of a fist; most common on the head, neck and shoulders, they may also occur in other locations. Cutaneous fibropapillomas caused by ''Deltapapillomavirus'' group have a nodular appearance. Although unsightly, most skin warts rarely cause problems except in show animals. However, large warts may bleed, potentially leading to secondary infections, and florid warts of the teat can cause mastitis and interfere with suckling and milking. Fibropapillomas can be troublesome when present in the genital area, causing pain and sometimes loss of reproductive functions as well as interfering with calving. Chronically immunosuppressed animals may develop extensive papillomatosis in the upper gastrointestinal tract, which can cause difficulties with eating and breathing. Warts contain large amounts of infectious virus which is relatively stable. Transmission between animals is common via, for example, fence posts or halters. Warts on the teats of lactating cows are readily transmitted to calves via abrasions. Contaminated tattooing or tagging equipment is another common source of infection.


Association with cancer


Cattle

BPV-4 causes
squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
s of the alimentary tract, and BPV-1/2 causes carcinomas and haemangioendotheliomas of the urinary bladder, in both cases in animals that have fed on
bracken Bracken (''Pteridium'') is a genus of large, coarse ferns in the family Dennstaedtiaceae. Ferns (Pteridophyta) are vascular plants that have alternating generations, large plants that produce spores and small plants that produce sex cells (eggs ...
('' Pteridium aquilinum''). Such cancers are common in locations where grazing land is infested with bracken, such as the western
Scottish Highlands The Highlands ( sco, the Hielands; gd, a’ Ghàidhealtachd , 'the place of the Gaels') is a historical region of Scotland. Culturally, the Highlands and the Lowlands diverged from the Late Middle Ages into the modern period, when Lowland Sco ...
, southern
Italy Italy ( it, Italia ), officially the Italian Republic, ) or the Republic of Italy, is a country in Southern Europe. It is located in the middle of the Mediterranean Sea, and its territory largely coincides with the homonymous geographical re ...
and the Nasampolai Valley in
Kenya ) , national_anthem = "Ee Mungu Nguvu Yetu"() , image_map = , map_caption = , image_map2 = , capital = Nairobi , coordinates = , largest_city = Nairobi , ...
. Bracken contains several
immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified in ...
s and
mutagen In genetics, a mutagen is a physical or chemical agent that permanently changes nucleic acid, genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can ca ...
s, including quercetin and
ptaquiloside Ptaquiloside is a norsesquiterpene glucoside produced by bracken ferns (majorly ''Pteridium aquilinum'') during metabolism. It is identified to be the main carcinogen of the ferns and to be responsible for their biological effects, such as bleedin ...
. Consumption of large quantities by cattle leads to an acute poisoning syndrome with symptoms of
bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
depletion, while at lower levels of long-term consumption it acts as a cancer cofactor.
Carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
is a multistep process; tumours also contain activated
Ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...
, as well as mutation or downregulation of the
tumour suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
genes '' p53'' in alimentary tract cancers and '' fragile histidine tetrads'' (''FHIT'') in urinary bladder cancers. Viral particles are not produced in either alimentary tract or urinary bladder tumours. These bracken-associated tumours might form a model for some types of human oesophageal cancer.
Human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
DNA has been detected in around 18% of squamous cell carcinomas of the oesophagus, and there is an association between exposure to or consumption of bracken (which is used as a foodstuff and herbal remedy in
South America South America is a continent entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere at the northern tip of the continent. It can also be described as the southe ...
,
China China, officially the People's Republic of China (PRC), is a country in East Asia. It is the world's most populous country, with a population exceeding 1.4 billion, slightly ahead of India. China spans the equivalent of five time zones and ...
,
Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...
,
Korea Korea ( ko, 한국, or , ) is a peninsular region in East Asia. Since 1945, it has been divided at or near the 38th parallel, with North Korea (Democratic People's Republic of Korea) comprising its northern half and South Korea (Republic o ...
and other countries) and risk of developing oesophageal cancer.


Other mammals

BPV-1 and BPV-2 can also induce
sarcoma A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcom ...
s and fibrosarcomas in other mammals, including equids (equine sarcoid) and, experimentally, rabbits, hamsters and mice (and reviewed in). Viral particles are not produced during infection of other species and, unlike in tumours associated with
human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
, the viral DNA is not integrated into the host genome.
Equine sarcoid Skin cancer, or neoplasia, is the most common type of cancer diagnosed in horses, accounting for 45Beuchner-Maxwell, "Skin tumors.", pg. 692 to 80% of all cancers diagnosed. Sarcoids are the most common type of skin neoplasm and are the most common ...
, a naturally occurring skin tumour affecting horses, donkeys and mules, is associated with strains of BPV-1/2 which may be equine specific. The lesions can occur anywhere on the body, often multiply, with the limbs, thorax–abdomen, head and paragenital areas being particularly commonly affected. The method of transmission is currently unclear; the involvement of face flies (''Musca autumnalis'') has been suggested, and transmission via contaminated tack is likely. The disease forms the only known example of natural cross-species infection by a papillomavirus. The involvement of BPV leads to hope that vaccination or
antiviral therapy Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do no ...
might be possible in the future for this common tumour.


Treatment, prophylaxis and prevention

Treatment is not usually required, as most warts eventually regress spontaneously. Surgical removal is possible but may lead to recurrence. Disinfection with
formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
of stalls, fence posts and other environmental virus reservoirs can prevent transmission.


Vaccination

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 verifie ...
s against BPV types 1, 2 and 4 have been developed by M. Saveria Campo and others. * Prophylactic vaccination (''i.e.'', vaccination of wart-free animals to prevent infection) with whole virus (e.g. formalin-killed wart tissue suspension), virus-like particles (L1 or L1+L2), L1 protein or (for BPV-4) L2 protein confers long-lasting protection against challenge with the same BPV type, but is generally ineffective against existing warts. Protection appears to be mediated via type-specific neutralising
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
. Vaccination of calves as early as 4–6 weeks might be necessary to prevent infection. * Therapeutic vaccination (''i.e.'', vaccination of animals with existing warts) with BPV-4 E7 or BPV-2 L2 induces early regression of warts. Wart rejection involves a
cell-mediated immune response Cell-mediated immunity or cellular immunity is an immune response that does not involve antibody, antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific Cytotoxic T cell, cytotoxic T-lymphocytes, and the rel ...
, with infiltration of the site by large numbers of
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s and
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s. These vaccine systems have served as models for the successful development of prophylactic vaccines against the
human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
types associated with
cervical In anatomy, cervical is an adjective that has two meanings: # of or pertaining to any neck. # of or pertaining to the female cervix: i.e., the ''neck'' of the uterus. *Commonly used medical phrases involving the neck are **cervical collar **cervic ...
and anal cancers. Both Gardasil (a quadrivalent prophylactic
HPV vaccine Human papillomavirus (HPV) vaccines are vaccines that prevent infection by certain types of human papillomavirus (HPV). Available HPV vaccines protect against either two, four, or nine types of HPV. All HPV vaccines protect against at least HP ...
licensed in 2006) and Cervarix (a bivalent prophylactic vaccine license in the EU in 2007 and USA in 2009) contain virus-like particles assembled from L1 protein, an approach successful against BPV, and both vaccines induce sustained immunity. Various therapeutic HPV vaccines based on E6, E7 and L2 are currently in early-stage clinical trials.


References


External links


Papillomavirus sequence data at Los Alamos National Laboratory
{{DEFAULTSORT:Bovine Papillomavirus Bovine diseases Horse diseases Papillomavirus Animal viral diseases