Jaagsiekte Sheep Retrovirus
Encyclopedia
Jaagsiekte sheep retrovirus (JSRV) is a betaretrovirus
which is the causative agent of a contagious lung cancer in sheep called Jaagsiekte
, or Ovine Pulmonary Adenocarcinoma
(OPA
).
(OPA) .The disease was called “Jaagsiekte”, after the Afrikaans words for “chase” (Jaag) and “sickness” (siekte), to describe the respiratory distress observed in an animal out of breath from being chased indicating the breathing difficulty that infected sheep have . Transmission of virus is through aerosol
spread between sheep.
Exogenous
infectious form of JSRV has an endogenous
counterpart which is present in the genomes of all sheep and goats..The sheep genome
has around 27 copies of endogenous retroviruses (enJSRVs) that is highly related to JSRV. Endogenous JSRV has several roles in the evolution of the domestic sheep as they are able to block the JSRV replication
cycle and play a critical role in sheep conceptus
development and placental morphogenesis
..
In spite of the fact that OPA resembles the human lung cancer , it has been found that the human lung cancer is not caused by any betaretrovirus
..Even though a possibility of viral etiology has been eliminated in Bronchio Alveolar cancer, understanding the molecular mechanisms leading to the transformation of lung epithelia by JSRV may be of interest in the context of therapeutic approaches in human lung cancers in general and bronchiolar-alveolar adenocarcinoma (BAC) in particular..
cells, in addition to the lung epithelia.Expression of the JSRV Envelope protein activates signalling cascades that promote cellular proliferation
and malignant
transformation of the cells. Initially, the tumour cells grow along the alveolar walls in a pattern reminiscent of human BAC, but subsequently become more invasive
and metastasize to the local lymph
nodes
. Larger tumours maybe necrotic and fibromatous at their centre.As the tumour grows, fluid production in the lung increases and this is likely to promote virus spread to other sheep. Only when the tumour reaches a size large enough to compromise lung function, do clinical signs appear. Critically,the majority of infected animals in endemic areas never show outward signs of infection, but they may be shedding virus, thus promoting inadvertent introduction of the disease into previously unaffected flocks and new geographical areas.
(LTR) on each end. There are 4 genes that encode the viral structural proteins. They are "gag" encoding the structural internal virion proteins comprising "matrix" (MA), "capsid" (CA) and "nucleocapsid"(NC); "pro", which encodes an aspartic protease
(PR); "pol", which encodes the" RT" and "integrase"(IN) enzymes; and "env", which encodes the "surface" (SU) and "transmembrane "(TM) envelope glycoproteins. The viral proteins are synthesized initially as large precursors and are later processed into the mature proteins by proteolytic cleavage. . An additional open reading frame
(ORF) was observed in the viral genome and has been called orfX and its function is undefined..
to a specific cell surface receptor molecule,"Hyal2". The entry of the JSRV core into the cytoplasm
activates reverse transcription, during which the single-stranded RNA genome is converted into a double-stranded DNA form and gets integrated as a provirus
into the host. Following integration, expression of JSRV RNA from the viral promoter in the LTR is controlled by the host transcriptional machine. Following transcription
and translation
of the viral genome, the new progeny
virus gets assembled at the plasma membrane and bud off from the host cell acquiring a lipid envelope and their "env" glycoproteins. Following release from the cell, the "Gag"-"Pro"-"Pol" polyproteins are cleaved into their mature forms by Protease
. This step maturation
is essential for the formation of infectious
particles.
for JSRV is hyaluronidase 2 (Hyal2), a glycophosphatidylinol(GPI)-anchored protein belonging to the hyaluronidase
family. Generally, oncogenic retroviruses cause transformation
of host cells mostly by insertional activation of a host proto oncogene
into an oncogene
. But JSRV is different in this aspect since its envelope glycoprotein ("env") by itself is an oncogene and this single protein was shown to be necessary and sufficient to induce lung tumors in sheep (J Virol. 2006 Aug;80(16):8030-7. Unlike the majority of retroviruses, JSRV entry into the host cell is pH-dependent. Thus oncogenic JSRV has borrowed features of both pH-dependent and pH-independent viruses for entry which involves both the receptor binding and a low pH for fusion transformation of host cells.
during T lymphocyte development and any JSRV-reactive T cells should be recognized as ‘anti-self’ and selectively
removed.Another hypothesis is that Tumor cells downregulate their Major Histocompatibility Class-I expression that might be the reason for the absence of any Virus-specific Cytotoxic T Cell response (CTL)
Betaretrovirus
A betaretrovirus is a genus of the retroviridae family. It has type B or type D morphology. The type B is common for a few exogenous, vertically transmitted and endogenous viruses of mice; some primate and sheep viruses are the type D....
which is the causative agent of a contagious lung cancer in sheep called Jaagsiekte
Jaagsiekte
Jaagsiekte is a chronic and contagious disease of the lungs in sheep and goats first described in 1865. Its name derives from Afrikaans and means "Chasing Sickness" such that animals afflicted with the disease are in respiratory distress as if they are out of breath from being chased. It is also...
, or Ovine Pulmonary Adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
(OPA
Jaagsiekte
Jaagsiekte is a chronic and contagious disease of the lungs in sheep and goats first described in 1865. Its name derives from Afrikaans and means "Chasing Sickness" such that animals afflicted with the disease are in respiratory distress as if they are out of breath from being chased. It is also...
).
Natural history
JSRV is the virus that is the etiologic agent responsible for contagious lung tumors in sheep called Ovine Pulmonary AdenocarcinomaAdenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
(OPA) .The disease was called “Jaagsiekte”, after the Afrikaans words for “chase” (Jaag) and “sickness” (siekte), to describe the respiratory distress observed in an animal out of breath from being chased indicating the breathing difficulty that infected sheep have . Transmission of virus is through aerosol
Aerosol
Technically, an aerosol is a suspension of fine solid particles or liquid droplets in a gas. Examples are clouds, and air pollution such as smog and smoke. In general conversation, aerosol usually refers to an aerosol spray can or the output of such a can...
spread between sheep.
Exogenous
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
infectious form of JSRV has an endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
counterpart which is present in the genomes of all sheep and goats..The sheep genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
has around 27 copies of endogenous retroviruses (enJSRVs) that is highly related to JSRV. Endogenous JSRV has several roles in the evolution of the domestic sheep as they are able to block the JSRV replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
cycle and play a critical role in sheep conceptus
Conceptus
Conceptus denotes the embryo and its adnexa or associated membranes . The conceptus includes all structures that develop from the zygote, both embryonic and extraembryonic...
development and placental morphogenesis
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
..
In spite of the fact that OPA resembles the human lung cancer , it has been found that the human lung cancer is not caused by any betaretrovirus
Betaretrovirus
A betaretrovirus is a genus of the retroviridae family. It has type B or type D morphology. The type B is common for a few exogenous, vertically transmitted and endogenous viruses of mice; some primate and sheep viruses are the type D....
..Even though a possibility of viral etiology has been eliminated in Bronchio Alveolar cancer, understanding the molecular mechanisms leading to the transformation of lung epithelia by JSRV may be of interest in the context of therapeutic approaches in human lung cancers in general and bronchiolar-alveolar adenocarcinoma (BAC) in particular..
Classification
JSRV belongs to the family Retroviridae, to the subfamily Orthoretrovirinae and the genus BetaretrovirusBetaretrovirus
A betaretrovirus is a genus of the retroviridae family. It has type B or type D morphology. The type B is common for a few exogenous, vertically transmitted and endogenous viruses of mice; some primate and sheep viruses are the type D....
Pathogenesis
JSRV is transmitted by the respiratory route and may also infect lymphocytes and myeloidMyeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
cells, in addition to the lung epithelia.Expression of the JSRV Envelope protein activates signalling cascades that promote cellular proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
and malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
transformation of the cells. Initially, the tumour cells grow along the alveolar walls in a pattern reminiscent of human BAC, but subsequently become more invasive
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and metastasize to the local lymph
Lymph
Lymph is considered a part of the interstitial fluid, the fluid which lies in the interstices of all body tissues. Interstitial fluid becomes lymph when it enters a lymph capillary...
nodes
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
. Larger tumours maybe necrotic and fibromatous at their centre.As the tumour grows, fluid production in the lung increases and this is likely to promote virus spread to other sheep. Only when the tumour reaches a size large enough to compromise lung function, do clinical signs appear. Critically,the majority of infected animals in endemic areas never show outward signs of infection, but they may be shedding virus, thus promoting inadvertent introduction of the disease into previously unaffected flocks and new geographical areas.
Genome structure
The genome of the exogenous virus is 7462 bases and has the classical "gag", "pol", "env" genome arrangement and is flanked by a long terminal repeatLong terminal repeat
Long terminal repeats are sequences of DNA that repeat hundreds or thousands of times. They are found in retroviral DNA and in retrotransposons, flanking functional genes...
(LTR) on each end. There are 4 genes that encode the viral structural proteins. They are "gag" encoding the structural internal virion proteins comprising "matrix" (MA), "capsid" (CA) and "nucleocapsid"(NC); "pro", which encodes an aspartic protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
(PR); "pol", which encodes the" RT" and "integrase"(IN) enzymes; and "env", which encodes the "surface" (SU) and "transmembrane "(TM) envelope glycoproteins. The viral proteins are synthesized initially as large precursors and are later processed into the mature proteins by proteolytic cleavage. . An additional 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...
(ORF) was observed in the viral genome and has been called orfX and its function is undefined..
Replication cycle
The initial attachment of JSRV to its target cell is mediated through the binding of the SU subunit of the Env glycoproteinGlycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
to a specific cell surface receptor molecule,"Hyal2". The entry of the JSRV core into the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
activates reverse transcription, during which the single-stranded RNA genome is converted into a double-stranded DNA form and gets integrated as a provirus
Provirus
A provirus is a virus genome that is integrated into the DNA of a host cell.This state can be a stage of virus replication, or a state that persists over longer periods of time as either inactive viral infections or an endogenous retrovirus. In inactive viral infections the virus will not replicate...
into the host. Following integration, expression of JSRV RNA from the viral promoter in the LTR is controlled by the host transcriptional machine. Following transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
and translation
Translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. Whereas interpreting undoubtedly antedates writing, translation began only after the appearance of written literature; there exist partial translations of the Sumerian Epic of...
of the viral genome, the new progeny
Offspring
In biology, offspring is the product of reproduction, of a new organism produced by one or more parents.Collective offspring may be known as a brood or progeny in a more general way...
virus gets assembled at the plasma membrane and bud off from the host cell acquiring a lipid envelope and their "env" glycoproteins. Following release from the cell, the "Gag"-"Pro"-"Pol" polyproteins are cleaved into their mature forms by Protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
. This step maturation
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
is essential for the formation of infectious
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
particles.
Receptor and Entry
The cellular receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for JSRV is hyaluronidase 2 (Hyal2), a glycophosphatidylinol(GPI)-anchored protein belonging to the hyaluronidase
Hyaluronidase
The hyaluronidases are a family of enzymes that degrade hyaluronic acid.In humans, there are six associated genes, including HYAL1, HYAL2, HYAL3, and PH-20/SPAM1.-Use as a drug:...
family. Generally, oncogenic retroviruses cause transformation
Malignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
of host cells mostly by insertional activation of a host proto oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
into an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
. But JSRV is different in this aspect since its envelope glycoprotein ("env") by itself is an oncogene and this single protein was shown to be necessary and sufficient to induce lung tumors in sheep (J Virol. 2006 Aug;80(16):8030-7. Unlike the majority of retroviruses, JSRV entry into the host cell is pH-dependent. Thus oncogenic JSRV has borrowed features of both pH-dependent and pH-independent viruses for entry which involves both the receptor binding and a low pH for fusion transformation of host cells.
Host Immune Response
An important feature of JSRV infection is the absence of any specific immune response from the host. A likely explanation is that the sheep are immunologically tolerant of JSRV antigens due to the expression of closely related endogenous JSRV proteins in the fetal thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
during T lymphocyte development and any JSRV-reactive T cells should be recognized as ‘anti-self’ and selectively
removed.Another hypothesis is that Tumor cells downregulate their Major Histocompatibility Class-I expression that might be the reason for the absence of any Virus-specific Cytotoxic T Cell response (CTL)