Bovine Papillomavirus Type 2 Infection Associated with Papillomatosis of the Amniotic Membrane in Water Buffaloes (Bubalus bubalis)

Multiple papillomatous nodules were observed scattered over the amniotic membrane in six water buffaloes that had recently aborted. Grossly, some of the nodules had multiple villous projections while others appeared as single prominent conical or cylindrical horns. Histology revealed folded hyperplastic and hyperkeratotic epithelium supported by a narrow fibro-vascular stalk. Using PCR, sequences of the bovine Deltapapillomavirus type 2 (BPV-2) E5 gene were amplified from the amniotic papillomas. Furthermore, expression of the E5 gene was detected using reverse transcription (RT)-PCR. Western blotting revealed BPV-2 E5 oncoprotein as well as L1 protein, suggesting both abortive and productive infection. Additionally, a functional complex composed of BPV-2 E5 oncoprotein and the phosphorylated PDGFβR was detected, which is consistent with the activation of PDGFβR by the interaction with BPV-2 E5 oncoprotein. These results demonstrate that BPV-2 can infect the amnion of water buffaloes and suggest that this infection may cause proliferation of the epithelial cells of the amnion. While the precise pathogenesis in uncertain, it is possible that BPV-2 infection of stratified squamous epithelial cells within squamous metaplasia foci and/or amniotic plaques could lead to papilloma formation. Papillomavirus-associated amniotic papillomas have not previously been reported in any species, including humans.

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Productive Infection of Bovine Papillomavirus Type 2 in the Urothelial Cells of Naturally Occurring Urinary Bladder Tumors in Cattle and Water Buffaloes

PLoS ONE ◽

10.1371/journal.pone.0062227 ◽

2013 ◽

Vol 8 (5) ◽

pp. e62227 ◽

Cited By ~ 22

Author(s):

Sante Roperto ◽

Valeria Russo ◽

Ayhan Ozkul ◽

Annunziata Corteggio ◽

Aylin Sepici-Dincel ◽

...

Keyword(s):

Urinary Bladder ◽

Productive Infection ◽

Bovine Papillomavirus ◽

Urothelial Cells ◽

Bladder Tumors ◽

Water Buffaloes ◽

Naturally Occurring

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Bovine papillomavirus type 2 infects the urinary bladder of water buffalo (Bubalus bubalis) and plays a crucial role in bubaline urothelial carcinogenesis

Journal of General Virology ◽

10.1099/vir.0.047662-0 ◽

2013 ◽

Vol 94 (2) ◽

pp. 403-408 ◽

Cited By ~ 34

Author(s):

Sante Roperto ◽

Valeria Russo ◽

Ayhan Ozkul ◽

Aylin Sepici-Dincel ◽

Paola Maiolino ◽

...

Keyword(s):

Urinary Bladder ◽

Cell Transformation ◽

Bubalus Bubalis ◽

Immunofluorescence Assay ◽

Receptor Interaction ◽

Bovine Papillomavirus ◽

Clinically Normal ◽

Bladder Carcinogenesis ◽

Β Receptor

Bovine papillomavirus type 2 (BPV-2) has been shown to infect and play a role in urinary bladder carcinogenesis of buffaloes grazed on pastures with ferns from the Marmara and Black Sea Regions of Turkey. BPV-2 DNA has been found in both neoplastic and non-neoplastic lesions of the urinary bladder. Furthermore, this virus may be a normal inhabitant of the urinary bladder since BPV-2 DNA has also been detected in clinically normal buffaloes. The viral activation by fern immunosuppressant or carcinogen may trigger the urothelial cell transformation. The E5 oncoprotein was solely detected in urothelial tumours and appeared to be co-localized with the overexpressed and phosphorylated platelet derived growth factor (PDGF) β receptor in a double-colour immunofluorescence assay. Our results indicate that the E5–PDGF β receptor interaction also occurs in spontaneous tumours of the bubaline urinary bladder, revealing an additional role of BPV-2 in bladder carcinogenesis of buffaloes.

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Bovine Papillomavirus Type 1 DNA and E5 Oncoprotein Expression in Water Buffalo Fibropapillomas

Veterinary Pathology ◽

10.1354/vp.08-vp-0222-p-fl ◽

2009 ◽

Vol 46 (4) ◽

pp. 636-641 ◽

Cited By ~ 35

Author(s):

O. Silvestre ◽

G. Borzacchiello ◽

D. Nava ◽

G. Iovane ◽

V. Russo ◽

...

Keyword(s):

Water Buffalo ◽

Electron Microscopic Examination ◽

Bubalus Bubalis ◽

Dermal Fibroblasts ◽

Epidermal Keratinocytes ◽

Long Control Region ◽

Bovine Papillomavirus ◽

Electron Microscopic ◽

E5 Oncoprotein ◽

Species Specific

Papillomas and fibropapillomas may occur in the skin and in different organs in animals. Ten different genotypes of bovine papillomavirus (BPV) have been identified. BPV-1 through BPV-10 are all strictly species-specific, but BPV-1/2 may also infect other species such as equids, inducing fibroblastic tumors. BPV-1 and BPV-2 are associated with fibropapillomas in cattle; these tumors are formed by excessive proliferation of virus-infected dermal fibroblasts and epidermal keratinocytes. Nine water buffalo (Bubalus bubalis) were examined for the presence of multiple cutaneous and perivulvar tumors. Cutaneous and perivulvar fibropapillomatosis were confirmed histologically. Negative-stain transmission electron microscopic examination revealed papillomavirus-like particles in the fibropapillomas, and papillomaviral DNA was also detected by the polymerase chain reaction. The amplified long control region (LCR) DNA sequence was identical to that of BPV-1. The BPV-1 E5 oncoprotein was strongly expressed in the tumor cells thus confirming a causal role of the virus. This article represents the first report of cutaneous, perivulvar, and vulvar fibropapilloma associated with BPV-1 infection in the water buffalo and describes another example of cross-species infection by BPV-1.

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Prohibitin 2 is Involved in Parkin-Mediated Mitophagy in Urothelial Cells of Cattle Infected with Bovine Papillomavirus

Pathogens ◽

10.3390/pathogens9080621 ◽

2020 ◽

Vol 9 (8) ◽

pp. 621

Author(s):

Francesca De Falco ◽

Ivan Gentile ◽

Pellegrino Cerino ◽

Anna Cutarelli ◽

Cornel Catoi ◽

...

Keyword(s):

Mitochondrial Membrane ◽

Embryonic Stem ◽

Bovine Papillomavirus ◽

Urothelial Cells ◽

Inner Mitochondrial Membrane ◽

Transmission Electron ◽

Mitochondrial Fractions ◽

E5 Oncoprotein ◽

Functional Complex ◽

Transcription Factor Eb

Prohibitin 2 (PHB2), an inner mitochondrial membrane (IMM) protein, has recently been identified as a novel receptor involved in parkin-mediated mitophagy. In the field of veterinary medicine, the role of PHB2 in parkin-mediated mitophagy was described, for the first time, in urothelial cells of cattle, naturally infected with bovine papillomavirus (BPV). The BPV2 and BPV13 E5 oncoprotein, responsible for abortive infections in urothelial cells, was detected by RT-PCR. Severe ultrastructural abnormalities of the inner mitochondrial membrane were detected using transmission electron microscopy. PHB2 formed a functional complex with PHB1. PHB2 was significantly overexpressed in mitochondrial fractions from urothelial mucosa samples taken from cattle harbouring BPV infection. PHB2 overexpression could be attributed to mitochondrial dysfunction, as its expression levels in the cytosolic, microsomal, and nuclear fractions were seen to be unmodified. Immunoprecipitation studies revealed the interaction between PHB2 and phosphorylated forms of both PINK1 and parkin. Furthermore, PHB2 interacted with LC3-II, a marker of autophagosomal membranes and autophagy receptors, such as p62 and optineurin. PHB2 was shown to interact with transcription factor EB (TFEB), which is activated following parkin-mediated mitophagy, and embryonic stem cell-expressed Ras (ERAS), a constitutive protein coded by ERas. Western blot analysis revealed a significant overexpression of unphosphorylated TFEB in mitochondrial and nuclear fractions from urothelial mucosa samples from cattle suffering from BPV infection. Finally, PHB2 interacted with ERAS, believed to be involved in mitophagosome maturation. Taken together, the molecular and ultrastructural findings of this study suggested that BPV infection is responsible for parkin-dependent mitophagy, in the pathway of which PHB2 plays a crucial role.

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Bovine Papillomavirus Type 2 Infection and a Series of Mesenchymal Tumors of the Urinary Bladder in Cattle

BioMed Research International ◽

10.1155/2013/814635 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Manuela Martano ◽

Franco Roperto ◽

Rita de Cassia Stocco ◽

Valeria Russo ◽

Giuseppe Borzacchiello ◽

...

Keyword(s):

Urinary Bladder ◽

Vascular Tumors ◽

Bovine Papillomavirus ◽

Mesenchymal Tumors ◽

Multinucleated Cells ◽

E5 Oncoprotein ◽

Papillary Endothelial Hyperplasia ◽

Tumor Like Lesions ◽

First Time

This report describes the histopathology of two hundred and fifty-three mesenchymal tumors of the urinary bladder in cattle grazing on lands rich in bracken fern. Approximately 80% were hemangiomas and angiosarcomas. Hemangioma (capillary, cavernous, and large vessels) was the most frequent mesenchymal tumor and was more common than angiosarcoma. Although the appearance of endothelial cells can vary remarkably, epithelioid angiosarcomas, often containing multinucleated cells, were the most frequent malignant vascular tumors. Hemangiopericytoma and tumors of muscle and soft connective tissue origin, alone and/or in association with tumor-like lesions, were less frequently seen. Furthermore, forty-five cases of intravascular papillary endothelial hyperplasia (IPEH), a lesion not previously reported in the urinary bladder of cattle, were also described. Bovine papillomavirus type-2 DNA was amplified in tumor samples. Forty vascular tumors were investigated by dual-labeling immunofluorescence, and, for the first time, a coexpression of E5 and platelet-derived growth factorβreceptor (PDGFβR) was shown to occur. The results show that the BPV-2 E5 oncoprotein binds to the activated form of the PDGFβreceptor thus playing an important role in mesenchymal as well as epithelial carcinogenesis of the urinary bladder. Furthermore, these findings demonstrate that BPV-2 infects both epithelial and mesenchymal cells.

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2. Redox Processing of the Viral Capsid Is Required for the Productive Infection of Airway Epithelial Cells by Adeno-Associated Virus Type 2

Molecular Therapy ◽

10.1016/s1525-0016(16)39405-9 ◽

2008 ◽

Vol 16 ◽

pp. S1

Keyword(s):

Epithelial Cells ◽

Virus Type ◽

Airway Epithelial Cells ◽

Productive Infection ◽

Viral Capsid ◽

Airway Epithelial ◽

Adeno Associated Virus

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Cooperative Transformation and Coexpression of Bovine Papillomavirus Type 1 E5 and E7 Proteins

Journal of Virology ◽

10.1128/jvi.75.1.513-521.2001 ◽

2001 ◽

Vol 75 (1) ◽

pp. 513-521 ◽

Cited By ~ 28

Author(s):

Joanna Bohl ◽

Bruce Hull ◽

Scott B. Vande Pol

Keyword(s):

Epithelial Cells ◽

Cellular Response ◽

Ectopic Expression ◽

Granular Cell ◽

Bovine Papillomavirus ◽

Basal Cells ◽

Cultured Epithelial Cells ◽

E5 Oncoprotein ◽

E7 Proteins

ABSTRACT Productively infected bovine fibropapillomas were examined for bovine papillomavirus type 1 (BPV-1) E7 localization. BPV-1 E7 was observed in the cytoplasm of basal and lower spinous epithelial cells, coexpressed in the cytoplasm of basal cells with the E5 oncoprotein. E7 was also observed in nucleoli throughout the basal and spinous layers but not in the granular cell layer. Ectopic expression of E7 in cultured epithelial cells gave rise to localization similar to that seen in productive fibropapillomas, with cytoplasmic and nucleolar expression observed. Consistent with the coexpression of E7 and E5 in basal keratinocytes, BPV-1 E7 cooperated with E5 as well as E6 in an anchorage independence transformation assay. While E5 is expressed in both basal and superficial differentiating keratinocytes, BPV-1 E7 is only observed in basal and lower spinous epithelial cells. Therefore, BPV-1 E7 may serve to modulate the cellular response of basal epithelial cells to E5 expression.

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Bovine Papillomavirus Type 2 (BPV-2) E5 Oncoprotein Binds to the Subunit D of the V1-ATPase Proton Pump in Naturally Occurring Urothelial Tumors of the Urinary Bladder of Cattle

PLoS ONE ◽

10.1371/journal.pone.0088860 ◽

2014 ◽

Vol 9 (2) ◽

pp. e88860 ◽

Cited By ~ 5

Author(s):

Sante Roperto ◽

Valeria Russo ◽

Giuseppe Borzacchiello ◽

Chiara Urraro ◽

Roberta Lucà ◽

...

Keyword(s):

Urinary Bladder ◽

Proton Pump ◽

Bovine Papillomavirus ◽

Naturally Occurring ◽

V1 Atpase ◽

E5 Oncoprotein ◽

Urothelial Tumors

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Bovine Papillomavirus Type 2 Infection and Microscopic Patterns of Urothelial Tumors of the Urinary Bladder in Water Buffaloes

BioMed Research International ◽

10.1155/2013/937918 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 9

Author(s):

Paola Maiolino ◽

Ayhan Özkul ◽

Aylin Sepici-Dincel ◽

Franco Roperto ◽

Gözde Yücel ◽

...

Keyword(s):

Urinary Bladder ◽

De Novo ◽

Low Grade ◽

Bovine Papillomavirus ◽

Water Buffaloes ◽

Early Protein ◽

Neoplastic Lesion ◽

Urothelial Tumors ◽

Invasive Carcinomas

Microscopic patterns of thirty-four urothelial tumors of the urinary bladder of water buffaloes from the Marmara and Black Sea Regions of Turkey are here described. All the animals grazed on lands rich in bracken fern. Histological diagnosis was assessed using morphological parameters recently suggested for the urinary bladder tumors of cattle. Papillary carcinoma was the most common neoplastic lesion (22/34) observed in this study, and low-grade carcinoma was more common (seventeen cases) than high-grade carcinoma (five cases). Papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), and invasive carcinomas were less frequently seen. Carcinoma in situ (CIS) was often detected associated with some papillary and invasive carcinomas. De novo (primary) CIS was rare representing 3% of tumors of this series. A peculiar feature of the most urothelial tumors was the presence in the tumor stroma of immune cells anatomically organized in tertiary lymphoid organs (TLOs). Bovine papillomavirus type-2 (PV-2) E5 oncoprotein was detected by molecular and immunohistochemistry procedures. Early protein, E2, and late protein, L1, were also detected by immunohistochemical studies. Morphological and molecular findings show that BPV-2 infection contributes to the development of urothelial bladder carcinogenesis also in water buffaloes.

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