Bovine papillomavirus
Encyclopedia
Bovine papillomavirus (BPV) is a group of DNA virus
es of the family Papillomaviridae
that are common in cattle
. Infection causes wart
s (papilloma
s and fibropapillomas) of the skin
and alimentary tract, and more rarely cancers of the alimentary tract and urinary bladder
. They are also thought to cause the skin tumour equine sarcoid in horse
s and donkey
s.
BPV provides an excellent model for studying papillomavirus molecular biology, and also allows the dissection of the processes by which this group of viruses cause cancer.
around 50–60 nm in diameter. The capsid is formed of the L1 and L2 structural proteins, with the L1 C-terminus exposed.
All BPVs have a circular 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
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).
A further thirteen putative BPVs have recently been identified; the novel viruses have yet to be assigned to subgroups.
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.
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
(Pteridium aquilinum
). Such cancers are common in locations where grazing land is infested with bracken, such as the western Scottish Highlands
, southern Italy
and the Nasampolai Valley in Kenya
. Bracken contains several immunosuppressant
s and mutagen
s, including quercetin
and ptaquiloside
. Consumption of large quantities by cattle leads to an acute poisoning syndrome with symptoms of bone marrow
depletion, while at lower levels of long-term consumption it acts as a cancer cofactor
. Carcinogenesis
is a multistep process; tumours also contain activated Ras
, as well as mutation or downregulation of the tumour suppressor
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
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
, China
, Japan
, Korea
and other countries) and risk of developing oesophageal cancer.
s and fibrosarcoma
s 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
, the viral DNA is not integrated into the host genome.
Equine sarcoid, 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
might be possible in the future for this common tumour.
of stalls, fence posts and other environmental virus reservoirs can prevent transmission.
s against BPV types 1, 2 and 4 have been developed by M. Saveria Campo and others.
These vaccine systems have served as models for the successful development of prophylactic vaccines against the human papillomavirus
types associated with cervical
and anal cancer
s. Both Gardasil
(a quadrivalent prophylactic HPV vaccine
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.
DNA virus
A DNA virus is a virus that has DNA as its genetic material and replicates using a DNA-dependent DNA polymerase. The nucleic acid is usually double-stranded DNA but may also be single-stranded DNA . DNA viruses belong to either Group I or Group II of the Baltimore classification system for viruses...
es of the family Papillomaviridae
Papillomaviridae
Papillomaviridae is an ancient taxonomic family of non-enveloped DNA viruses, collectively known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected birds and mammals, but also a small number...
that are common in cattle
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
. Infection causes wart
Wart
A wart is generally a small, rough growth, typically on a human’s hands or feet but often other locations, that can resemble a cauliflower or a solid blister. They are caused by a viral infection, specifically by human papillomavirus 2 and 7. There are as many as 10 varieties of warts, the most...
s (papilloma
Papilloma
Papilloma refers to a benign epithelial tumor growing exophytically in finger-like fronds. In this context papilla refers to the projection created by the tumor, not a tumor on an already existing papilla . When used without context, it frequently refers to infections caused by human...
s and fibropapillomas) of the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
and alimentary tract, and more rarely cancers of the alimentary tract and urinary bladder
Urinary bladder
The urinary bladder is the organ that collects urine excreted by the kidneys before disposal by urination. A hollow muscular, and distensible organ, the bladder sits on the pelvic floor...
. They are also thought to cause the skin tumour equine sarcoid in horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...
s and donkey
Donkey
The donkey or ass, Equus africanus asinus, is a domesticated member of the Equidae or horse family. The wild ancestor of the donkey is the African Wild Ass, E...
s.
BPV provides an excellent model for studying papillomavirus molecular biology, and also allows the dissection of the processes by which this group of viruses cause cancer.
Structure and genetic organisation
Like other papillomaviruses, BPVs are small non-enveloped viruses with an icosahedral capsidCapsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
around 50–60 nm in diameter. The capsid is formed of the L1 and L2 structural proteins, with the L1 C-terminus exposed.
All BPVs have a circular double-stranded DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
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
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...
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 ungulateUngulateUngulates are several groups of mammals, most of which use the tips of their toes, usually hoofed, to sustain their whole body weight while moving. They make up several orders of mammals, of which six to eight survive...
s (e.g. deer papillomavirus, European elk papillomavirus, ovine papillomavirus 1,2) are also found in this group. Like all members of the papillomavirus class, these viruses infect only keratinocytes (epithelial cells); however, unlike other papillomaviruses, they cause proliferation of both keratinocytes and fibroblastFibroblastA fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s, causing benign fibropapillomas involving both the epitheliumEpitheliumEpithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
and the underlying dermisDermisThe dermis is a layer of skin between the epidermis and subcutaneous tissues, and is composed of two layers, the papillary and reticular dermis...
. 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 epitheliumEpitheliumEpithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
. The specificity of the types differs:- BPV-3 infects skin
- BPV-4 infects the upper alimentary tract
- BPV-6 infects teats and udders
- Epsilonpapillomavirus 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 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
Mastitis
Mastitis is the inflammation of breast tissue. S. aureus is the most common etiological organism responsible, but S. epidermidis and streptococci are occasionally isolated as well.-Terminology:...
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.
Cattle
BPV-4 causes squamous cell carcinomaSquamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
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
Bracken are several species of large, coarse ferns of the genus Pteridium. Ferns are vascular plants that have alternating generations, large plants that produce spores and small plants that produce sex cells . Brackens are in the family Dennstaedtiaceae, which are noted for their large, highly...
(Pteridium aquilinum
Pteridium aquilinum
Pteridium aquilinum is a species of fern occurring in temperate and subtropical regions throughout much of the northern hemisphere....
). Such cancers are common in locations where grazing land is infested with bracken, such as the western Scottish Highlands
Scottish Highlands
The Highlands is an historic region of Scotland. The area is sometimes referred to as the "Scottish Highlands". It was culturally distinguishable from the Lowlands from the later Middle Ages into the modern period, when Lowland Scots replaced Scottish Gaelic throughout most of the Lowlands...
, southern Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
and the Nasampolai Valley in Kenya
Kenya
Kenya , officially known as the Republic of Kenya, is a country in East Africa that lies on the equator, with the Indian Ocean to its south-east...
. Bracken contains several immunosuppressant
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...
s and mutagen
Mutagen
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...
s, including quercetin
Quercetin
Quercetin , a flavonol, is a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods.-Occurrence:...
and ptaquiloside
Ptaquiloside
Ptaquiloside, the major toxin of bracken, was first isolated in 1983, and its chemical stereostructure was determined to be norsesquiterpene glucoside of illudane type by Yamada and co-workers....
. Consumption of large quantities by cattle leads to an acute poisoning syndrome with symptoms of bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
depletion, while at lower levels of long-term consumption it acts as a cancer cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
. Carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
is a multistep process; tumours also contain activated Ras
Ras
Ras is the name given to a family of related proteins found inside cells, including human cells. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells...
, as well as mutation or downregulation of the tumour suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
genes p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
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
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
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
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...
, China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
, Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, Korea
Korea
Korea ) is an East Asian geographic region that is currently divided into two separate sovereign states — North Korea and South Korea. Located on the Korean Peninsula, Korea is bordered by the People's Republic of China to the northwest, Russia to the northeast, and is separated from Japan to the...
and other countries) and risk of developing oesophageal cancer.
Other mammals
BPV-1 and BPV-2 can also induce sarcomaSarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
s and fibrosarcoma
Fibrosarcoma
Fibrosarcoma is a malignant tumor derived from fibrous connective tissue and characterized by immature proliferating fibroblasts or undifferentiated anaplastic spindle cells.Usually in males ages 30 to 40. Originates in fibrous tissues of the bone. Invades long or flat bones such as femur, tibia,...
s 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
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
, the viral DNA is not integrated into the host genome.
Equine sarcoid, 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)
Musca autumnalis
Musca autumnalis, the face fly or autumn house-fly, is a pest of cattle and horses- Description :The face fly is similar to the closely related house fly. Slightly larger, averaging about 7 - 8 mm long and Grey in colour with 4 dark stripes on the thorax, with a grey-black patterned abdomen...
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 drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
might be possible in the future for this common tumour.
Treatment, prophylaxis & prevention
Treatment is not usually required, as most warts eventually regress spontaneously. Surgical removal is possible but may lead to recurrence. Disinfection with formaldehydeFormaldehyde
Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...
of stalls, fence posts and other environmental virus reservoirs can prevent transmission.
Vaccination
VaccineVaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
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 antibodiesAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
. 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, with infiltration of the site by large numbers of lymphocyteLymphocyteA lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s and macrophageMacrophageMacrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s.
These vaccine systems have served as models for the successful development of prophylactic vaccines against the human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
types associated with cervical
Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
and anal cancer
Anal cancer
Anal cancer is a type of cancer which arises from the anus, the distal orifice of the gastrointestinal tract. It is a distinct entity from the more common colorectal cancer. The etiology, risk factors, clinical progression, staging, and treatment are all different. Anal cancer is typically a...
s. Both Gardasil
Gardasil
Gardasil , also known as Gardisil or Silgard, is a vaccine for use in the prevention of certain types of human papillomavirus , specifically HPV types 6, 11, 16 and 18. HPV types 16 and 18 cause an estimated 70% of cervical cancers, and are responsible for most HPV-induced anal, vulvar, vaginal,...
(a quadrivalent prophylactic HPV vaccine
HPV vaccine
The human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...
licensed in 2006) and Cervarix
Cervarix
Cervarix is a vaccine against certain types of cancer-causing human papillomavirus .Cervarix is designed to prevent infection from HPV types 16 and 18, that cause about 70% of cervical cancer cases. These types also cause some other genital cancers and some oropharyngeal cancers...
(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.