Specific in vivo expression in type II pneumocytes of the jaagsiekte sheep retrovirus long terminal repeat in transgenic mice

Dakessian, Raffy M.; Fan, Hung

doi:10.1016/j.virol.2007.10.035

Cited by 11 publications

(6 citation statements)

References 54 publications

(67 reference statements)

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“…The JSRV LTRs contains lung-specific enhancer binding motifs that are preferentially active in cell lines derived from transformed type 2 pneumocytes [80] – [83] . In addition, in transgenic mice, reporter gene expression driven by the JSRV LTR has been detected specifically in type 2 pneumocytes [84] . Thus, JSRV-host equilibrium has been reached by a combination of factors.…”

Section: Discussionmentioning

confidence: 99%

Lung Adenocarcinoma Originates from Retrovirus Infection of Proliferating Type 2 Pneumocytes during Pulmonary Post-Natal Development or Tissue Repair

et al. 2011

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Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer.

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Section: Discussionmentioning

confidence: 99%

Lung Adenocarcinoma Originates from Retrovirus Infection of Proliferating Type 2 Pneumocytes during Pulmonary Post-Natal Development or Tissue Repair

et al. 2011

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“…For example, in transgenic mice carrying a beta-galactosidase reporter gene under the control of the JSRV LTR, reporter activity was predominantly restricted to type II pneumocytes (16). In a separate study, infection of mice with adeno-associated virus vectors expressing JSRV Env resulted in tumors with a bronchioloalveolar distribution similar to those seen in sheep (87).…”

mentioning

confidence: 95%

Jaagsiekte Sheep Retrovirus Infects Multiple Cell Types in the Ovine Lung

Martineau

Cousens

Imlach

et al. 2011

J Virol

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“…In previous studies, the JSRV LTR was found to be preferentially active in MLE-15 and mtCC1-2 mouse cell lines derived from alveolar type II pneumocytes (ATII) and Clara cells, respectively (22,23,27), while in transgenic mice carrying a bacterial ␤-galactosidase gene driven by the JSRV LTR, expression was limited to ATII cells and not detected in Clara cells or in any other tissues (8). However, none of these studies examined the function of the JSRV LTR in the nasal epithelium.…”

Section: Discussionmentioning

confidence: 94%

Jaagsiekte Sheep Retrovirus and Enzootic Nasal Tumor Virus Promoters Drive Gene Expression in All Airway Epithelial Cells of Mice but Only Induce Tumors in the Alveolar Region of the Lungs

Linnerth-Petrik

Halbert

et al. 2011

J Virol

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Jaagsiekte sheep retrovirus (JSRV) induces tumors in the distal airways of sheep and goats, while the closely related enzootic nasal tumor virus type 1 (ENTV-1) and ENTV-2 induce tumors in the nasal epithelium of sheep and goats, respectively. When expressed using a strong Rous sarcoma virus promoter, the envelope proteins of these viruses induce tumors in the respiratory tract of mice, but only in the distal airway. To examine the role of the retroviral long terminal repeat (LTR) promoters in determining tissue tropism, adeno-associated virus (AAV) vectors expressing alkaline phosphatase under the control of the JSRV, ENTV-1, or ENTV-2 LTRs were generated and administered to mice. The JSRV LTR was active in all airway epithelial cells, while the ENTV LTRs were active in the nasal epithelium and alveolar type II cells but poorly active in tracheal and bronchial epithelial cells. When vectors were administered systemically, the ENTV-1 and -2 LTRs were inactive in major organs examined, whereas the JSRV showed high-level activity in the liver. When a putative transcriptional enhancer from the 3 end of the env gene was inserted upstream of the JSRV and ENTV-1 LTRs in the AAV vectors, a dramatic increase in transgene expression was observed. However, intranasal administration of AAV vectors containing any combination of ENTV or JSRV LTRs and Env proteins induced tumors only in the lower airway. Our results indicate that mice do not provide an adequate model for nasal tumor induction by ENTV despite our ability to express genes in the nasal epithelium.Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are closely related oncogenic betaretroviruses that infect sheep and goats. These viruses share greater than 90% sequence identity and utilize the same cellular receptor for virus attachment and entry (10, 32), yet they cause distinctly different diseases. JSRV transforms secretory epithelial cells of the distal lung leading to ovine pulmonary adenocarcinoma (OPA) (28,34). ENTV also transforms secretory epithelial cells, although in this case the target cells are located in the nasal mucosa and lead to the formation of a neoplastic disease called enzootic nasal adenocarcinoma (ENA) (9). Two distinct viruses have been implicated in the etiology of ENA, one in sheep (ENTV-1) and one in goats (ENTV-2), and the genomic sequences of both have been determined (7,26,38).It is currently not known how such different diseases result from infection by these closely related retroviruses. Experimental induction of OPA in sheep has been demonstrated using a molecular clone of JSRV (30); however, the lack of a cell culture system capable of propagating ENTV, the fact that an infectious molecular clone of ENTV has not yet been published, and the limitation that experiments using sheep are expensive, have made it difficult to study the mechanism of disease tropism in sheep. Therefore, we developed a model to study JSRV and ENTV tumorigenesis in mice using adenoassociated virus (AAV) vectors (41). AAV vectors made w...

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Specific in vivo expression in type II pneumocytes of the jaagsiekte sheep retrovirus long terminal repeat in transgenic mice

Cited by 11 publications

References 54 publications

Lung Adenocarcinoma Originates from Retrovirus Infection of Proliferating Type 2 Pneumocytes during Pulmonary Post-Natal Development or Tissue Repair

Lung Adenocarcinoma Originates from Retrovirus Infection of Proliferating Type 2 Pneumocytes during Pulmonary Post-Natal Development or Tissue Repair

Jaagsiekte Sheep Retrovirus Infects Multiple Cell Types in the Ovine Lung

Jaagsiekte Sheep Retrovirus and Enzootic Nasal Tumor Virus Promoters Drive Gene Expression in All Airway Epithelial Cells of Mice but Only Induce Tumors in the Alveolar Region of the Lungs

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