Қой өкпесінің қатерлі ісін қоздыратын вирус (Jaagsiekte)

Species of virus

Jaagsiekte sheep retrovirus (JSRV) is a betaretrovirus which is the causative agent of a contagious lung cancer in sheep, called ovine pulmonary adenocarcinoma.

JSRV is the virus that is the cause of the contagious lung tumors in sheep called ovine pulmonary adenocarcinoma (OPA). The disease has also been 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 experienced by infected sheep. Transmission of virus is through aerosol spread between sheep. The 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 are closely 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. Although OPA resembles human lung cancer, human lung cancer is not known to be caused by betaretroviruses. Even though a possibility of a viral cause has been eliminated in bronchoalveolar 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 bronchoalveolar adenocarcinoma (BAC) in particular.

JSRV belongs to the family Retroviridae, to the subfamily Orthoretrovirinae and the genus Betaretrovirus.

JSRV is transmitted by the respiratory route and may also infect lymphocytes and myeloid 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 may be 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.

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 repeat (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. 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.

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 to JSRV antigens due to the expression of closely related endogenous JSRV proteins in the fetal thymus 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, possibly being the reason for the absence of any virus specific cytotoxic T cell response (CTL). There are 27 known copies of enJSRV in the sheep genome, of which five show intact sequences found in all retroviruses. An example of this protection is seen in ovine endometrial epithelium where the high expression of enJSVR prevents exogenous JSVR from entering the cells via blocking the common receptor to both, HYAL2. Experiments have found that the enJSRV envelope regulates trophoblast growth and differentiation within the peri implantation conceptus. It was discovered that enJSRVs are expressed in the trophectoderm cells of the placenta. Their expression coincides with the key events of conceptus elongation and onset of trophoblast giant binucleate cells (BNC) differentiation. This stimulates both the corpus luteum to continue to secrete progesterone and the onset of implantation. During the formation of the human placenta syncytiotrophoblast, by fusion of mononuclear cytotrophoblasts, human syncytins are specifically expressed. The syncytins are fusogenic when expressed in vitro, supporting the hypothesis that they are involved in placental morphogenesis. These observations support the theory that an ancient retroviral infection had important consequences for mammalian evolution. The involvement of the betaretrovirus enJSRV in the sheep conceptus trophoblasts further argues for its involvement in sheep placentation.

Research surrounding endogenous retroviruses supports the idea that they may play critical roles in conceptus growth, placental differentiation and cell fusion in mammals. The morphological aspects of binucleate cell differentiation in ruminants such as sheep are well characterised, but the mechanisms are not well defined though evidence shows that enJSRV RNA and HYAL2 mRNA are co expressed in the binucleate cell and multinucleated syncytiotrophoblasts throughout gestation.