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. 2013 Oct;87(19):10752-62.
doi: 10.1128/JVI.01472-13. Epub 2013 Jul 31.

Host species barriers to Jaagsiekte sheep retrovirus replication and carcinogenesis

Marco Caporale  1 , Henny Martineau, Marcelo De las Heras, Claudio Murgia, Robert Huang, Patrizia Centorame, Gabriella Di Francesco, Luigina Di Gialleonardo, Thomas E Spencer, David J Griffiths, Massimo Palmarini
Affiliations

Host species barriers to Jaagsiekte sheep retrovirus replication and carcinogenesis

Marco Caporale et al. J Virol. 2013 Oct.

Abstract

Understanding the factors governing host species barriers to virus transmission has added significantly to our appreciation of virus pathogenesis. Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA), a transmissible lung cancer of sheep that has rarely been found in goats. In this study, in order to further clarify the pathogenesis of OPA, we investigated whether goats are resistant to JSRV replication and carcinogenesis. We found that JSRV induces lung tumors in goats with macroscopic and histopathological features that dramatically differ from those in sheep. However, the origins of the tumor cells in the two species are identical. Interestingly, in experimentally infected lambs and goat kids, we revealed major differences in the number of virus-infected cells at early stages of infection. These differences were not related to the number of available target cells for virus infection and cell transformation or the presence of a host-specific immune response toward JSRV. Indeed, we also found that goats possess transcriptionally active endogenous retroviruses (enJSRVs) that likely influence the host immune response toward the exogenous JSRV. Overall, these results suggest that goat cells, or at least those cells targeted for viral carcinogenesis, are not permissive to virus replication but can be transformed by JSRV.

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Figures

Fig 1
Fig 1
Macroscopic appearance of lung tumors induced by JSRV in lambs and goat kids. (A) Lungs from experimentally infected lambs at 5 months postinfection show extensive tumor lesions (some indicated by arrows), purple to greyish in color, infiltrating different lobes of the lungs. (B) Cross-section of lungs from an infected lamb reveals extensive infiltration of the neoplasm throughout the organ. (C) Lungs from an experimentally infected goat kid show well-circumscribed pale small nodules (arrows indicate some of them) well delimitated from the surrounding healthy pulmonary parenchyma. (D) Higher-magnification picture of lesions from an infected kid.
Fig 2
Fig 2
Histopathology of lung sections collected from lambs and goat kids experimentally infected with JSRV. (A) Tissue section (stained with hematoxylin and eosin) collected from the lungs of an experimentally infected lamb showing the presence of numerous neoplastic foci (indicated by arrows) in close proximity. (B) Tissue section (stained with hematoxylin and eosin) collected from the lungs of an experimentally infected goat kid with a well-isolated expanding neoplastic nodule (indicated by arrows). (C) Immunohistochemistry of lung section from an experimental infected lamb (same as panel A) showing labeling of JSRV Env in tumor cells (characterized by the intracytoplasmic brown color). (D) Immunohistochemistry of lung section from an experimental infected goat kid (same as panel B) showing labeling of JSRV Env in tumor cells. (E and F) Immunohistochemistry of lung section from an experimental infected lamb (E) or goat kid (F) showing labeling of JSRV Gag in tumor cells. (G and H) Immunohistochemistry of lung section from an experimental infected goat kid shows expression in a few cells (see arrows) infiltrating the tumor expressing MHC-II (E) or CD8 (F) cell markers.
Fig 3
Fig 3
JSRV more readily infects lung cells in experimentally infected lambs than in goat kids. (A to D) Immunohistochemistry of JSRV Env+ cells in lung sections collected from experimentally infected lambs (A and B) and kids (C and D) 9 days postinfection. JSRV-infected cells are characterized by dark intracytoplasmic brown staining. (E) Box-and-whisker plot showing the number of JSRV Env+ clusters per animal as detected by immunohistochemistry in four lambs and four goat kids at 9 days postinfection. Data represent analysis of 8 lung sections for each animal. (F) Box-and-whisker plot showing the total number of JSRV Env+ cells per animal as detected by immunohistochemistry. Lung sections (n = 8) were analyzed for each animal (as with panel E). (G) Graph indicating the number of clusters in infected lambs and goat kids formed by either 1 to 2, 3 to 4, 5 to 9, or more than 10 JSRV Env+ cells.
Fig 4
Fig 4
Phenotype of JSRV-infected cells in experimentally inoculated goat kids. (A to C) Confocal microscopy of lung sections from goat kids experimentally infected with JSRV and collected at either 5 months (A) or 9 days (B and C) postinfection. In panels A and B, immunofluorescence was carried out using antibodies toward SP-C (shown in red) and JSRV Env (shown in green), while in panel C, antibodies toward the Clara cell marker CC10 and JSRV Env were used. Nuclei were stained with DAPI and are shown in blue. Arrows indicate cells expressing JSRV Env.
Fig 5
Fig 5
Number of proliferating SP-C+ and CC10+ cells in healthy goat kids. (A and B) Analysis of proliferating type 2 pneumocytes (LAPCs) was performed by counting SP-C/Ki67 doubly positive cells in 4-day-old goat kids by confocal microscopy as described in Materials and Methods. Sections (n = 10) for each animal were analyzed by confocal microscopy, and numbers of doubly positive cells were normalized to the sectioned area. Results shown are the average numbers of SP-C+ Ki67+ cells (± SD) per section for both groups of animals. (B) Representative image of a lung section from a 4-day-old goat kid analyzed by confocal microscopy using antibodies toward SP-C (shown in red) and Ki67 (shown in green). Nuclei were stained with DAPI and are shown in blue. Note that Ki67 is a nuclear marker, and therefore the positive signal appears in turquoise in the merged image. Arrows indicate SP-C+ Ki67+ cells. (C) Analysis of proliferating Clara cells was performed by counting the number of CC10+ Ki67+ cells in 100 terminal bronchioli per each animal. Results shown are the average numbers of CC10+ Ki67+ cells (± SD) per 100 terminal bronchioli for both groups of animals. (D) Representative image of a lung section from a 2-day-old goat kid analyzed by confocal microscopy using antibodies toward CC10 (shown in green) and Ki67 (shown in red). Nuclei were stained with DAPI and are shown in blue. Arrows indicate CC10+ Ki67+ cells.
Fig 6
Fig 6
Neutralization activities of lamb and kid sera against retroviral vectors pseudotyped with JSRV Env. Sera collected prior to infection and at the indicated times postinfection were tested at a 1:10 dilution against MLV-LacZ vectors pseudotyped with JSRV Env. The infectivity of the serum-treated vector is shown relative to the infectivity of the untreated vector (100%). Sera were tested in triplicate. Error bars show standard deviations. C1, C2, and C3 are mock-inoculated control animals.
Fig 7
Fig 7
Expression of enJSRVs in the goat uterus. In situ localization of enJSRV RNA expression in the endometrium of pregnant and cyclic does as indicated in the figure. Cross sections of the endometrium were hybridized with radiolabeled antisense or sense ovine enJSRV env cRNA probes. Transcripts were visualized by liquid emulsion autoradiography for 1 week and imaged under bright-field (left) or dark-field (right) illumination. Numbers indicate the gestational or cyclic day when samples were collected. LE, luminal epithelium; GE, glandular epithelium; Tr, trophectoderm; sGE, superficial glandular epithelium.
Fig 8
Fig 8
Model for pathogenesis of OPA lesions in sheep and goats. (A) Young lambs have many available target cells for JSRV-induced cell transformation (LAPCs) that are dividing and consequently can be infected and transformed by the virus. Transformed cells produce infectious virus that can then infect and transform other target cells, resulting in many satellite and coalescing lesions giving rise to tumors with an invasive phenotype. This is also known as the “classic” OPA phenotype. (B) Experimental inoculation of young lambs with a replication-incompetent JSRV (JS-RD) or goat kids with wild-type JSRV results in infection and transformation of target cells that do not produce infectious virus, hence the “expanding” phenotype, where tumor nodules are derived from a single transformed cell. The tumor phenotype in panel B is similar to the “atypical” tumor phenotype observed occasionally in adult sheep.
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