80 results on '"Borgogna C"'
Search Results
2. Identification of the skin virome in a boy with widespread human papillomavirus-2-positive warts that completely regressed after administration of tetravalent human papillomavirus vaccine
- Author
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Landini, M. M., Borgogna, C., Peretti, A., Doorbar, J., Griffin, H., Mignone, F., Lai, A., Urbinati, L., Matteelli, A., Gariglio, M., and De Andrea, M.
- Published
- 2015
- Full Text
- View/download PDF
3. Characterization of skin lesions induced by skin-tropic α- and β-papillomaviruses in a patient with epidermodysplasia verruciformis
- Author
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Borgogna, C., Landini, M. M., Lanfredini, S., Doorbar, J., Bouwes Bavinck, J. N., Quint, K. D., de Koning, M. N.C., Genders, R. E., and Gariglio, M.
- Published
- 2014
- Full Text
- View/download PDF
4. Analysis of human β-papillomavirus and Merkel cell polyomavirus infection in skin lesions and eyebrow hair bulbs from a cohort of patients with chronic lymphocytic leukaemia
- Author
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Peretti, A., Borgogna, C., Rossi, D., De Paoli, L., Bawadekar, M., Zavattaro, E., Boldorini, R., De Andrea, M., Gaidano, G., and Gariglio, M.
- Published
- 2014
- Full Text
- View/download PDF
5. Redistribution of the nuclear protein IFI16 into the cytoplasm of ultraviolet B-exposed keratinocytes as a mechanism of autoantigen processing
- Author
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Costa, S., Borgogna, C., Mondini, M., De Andrea, M., Meroni, P. L., Berti, E., Gariglio, M., and Landolfo, S.
- Published
- 2011
- Full Text
- View/download PDF
6. The Human Cytomegalovirus Tegument Protein pp65 (pUL83) Dampens Type I Interferon Production by Inactivating the DNA Sensor cGAS without Affecting STING [*Biolatti M, Dell'Oste V* co-first authors]
- Author
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Biolatti, M, Dell'Oste, V, Pautasso, S, Gugliesi, F, von Einem, J, Krapp, C, Jakobsen, Mr, Borgogna, C, Gariglio, M, De Andrea, M, and Landolfo, S
- Published
- 2018
7. HPV8 field cancerization in a transgenic mouse model is due to Lrig1+Keratinocyte stem cell expansion
- Author
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Lanfredini, S, Olivero, C, Borgogna, C, Calati, F, Powell, K, Davies, K, De Andrea, M, Harries, S, Tang, H, Pfister, H, Gariglio, M, and Patel, G
- Subjects
WT, wild type ,Keratinocytes ,Actinic ,Skin Neoplasms ,Mice, Transgenic ,HPV, human papillomavirus ,Nerve Tissue Proteins ,KSC, keratinocyte stem cell ,Biochemistry ,Transgenic ,EV, epidermodysplasia verruciformis ,Mice ,Experimental ,Neoplasms ,SCC, cutaneous squamous cell carcinoma ,Animals ,TA, transcriptional activation ,Papillomaviridae ,Molecular Biology ,Cell Proliferation ,Membrane Glycoproteins ,integumentary system ,HF, hair follicle ,IFE, interfollicular epidermis ,Neoplasms, Experimental ,Keratosis ,Cell Biology ,Keratosis, Actinic ,AK, actinic keratosis ,Neoplastic Stem Cells ,2708 ,Tumor Biology ,Original Article - Abstract
β-Human papillomaviruses (HPVs) cause near ubiquitous latent skin infection within long-lived hair follicle (HF) keratinocyte stem cells. In patients with epidermodysplasia verruciformis, β-HPV viral replication is associated with skin keratosis and cutaneous squamous cell carcinoma. To determine the role of HF keratinocyte stem cells in β-HPV-induced skin carcinogenesis, we utilized a transgenic mouse model in which the keratin 14 promoter drives expression of the entire HPV8 early region (HPV8tg). HPV8tg mice developed thicker skin in comparison with wild-type littermates consistent with a hyperproliferative epidermis. HF keratinocyte proliferation was evident within the Lrig1+ keratinocyte stem cell population (69 vs. 55%, P < 0.01, n = 7), and not in the CD34+, LGR5+, and LGR6+ keratinocyte stem cell populations. This was associated with a 2.8-fold expansion in Lrig1+ keratinocytes and 3.8-fold increased colony-forming efficiency. Consistent with this, we observed nuclear p63 expression throughout this population and the HF infundibulum and adjoining interfollicular epidermis, associated with a switch from p63 transcriptional activation isoforms to ΔNp63 isoforms in HPV8tg skin. Epidermodysplasia verruciformis keratosis and in some cases actinic keratoses demonstrated similar histology associated with β-HPV reactivation and nuclear p63 expression within the HF infundibulum and perifollicular epidermis. These findings would suggest that β-HPV field cancerization arises from the HF junctional zone and predispose to squamous cell carcinoma.
- Published
- 2017
8. The transgenic HPV8 mouse skin is associated with LRIG1 keratinocyte stem cell expansion
- Author
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Patel, G., Lanfredini, S., Olivera, C., Borgogna, C., Calati, F., Powell, K., Davies, K-J., De Andrea, M., Harries, S., Tang, H. K. C., Pfister, H., Gariglio, M., Patel, G., Lanfredini, S., Olivera, C., Borgogna, C., Calati, F., Powell, K., Davies, K-J., De Andrea, M., Harries, S., Tang, H. K. C., Pfister, H., and Gariglio, M.
- Published
- 2017
9. Role of polyomavirus BK in the carcinogenesis of urothelial and renal tumours in kidney transplant recipients
- Author
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Poletti, F., primary, Borgogna, C., additional, Billia, M., additional, Zacchero, M., additional, Boldorini, R., additional, Cantaluppi, V., additional, Gariglio, M., additional, and Volpe, A., additional
- Published
- 2017
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10. Human Beta-papillomavirus infection and keratinocyte carcinomas
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Quint, K.D., Genders, R.E., Koning, M.N.C. de, Borgogna, C., Gariglio, M., Bavinck, J.N.B., Doorbar, J., and Feltkamp, M.C.
- Subjects
Beta-papillomavirus ,squamous cell carcinoma ,skin cancer ,basal cell carcinoma ,human papillomavirus ,keratinocyte carcinoma - Published
- 2015
11. Restriction of HPV18 Replication in the Nucleus by IFI16: what about Innate Sensing?
- Author
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DE ANDREA, Marco, Albertini, S., Calati, F., LO CIGNO, Irene, Borgogna, C., Johnson, K., Chandran, B., Landolfo, Santo Giuseppe, and Gariglio, M.
- Published
- 2015
12. Restriction of HPV18 replication in the nucleus by IFI16: what about innate sensing?
- Author
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Albertini, S., LO CIGNO, Irene, DE ANDREA, Marco, Borgogna, C., Peretti, A., Gherardi, G., Johnson, K. E., Chandran, B., Landolfo, Santo Giuseppe, and Gariglio, M.
- Published
- 2015
13. Identification of the skin virome in a young boy with widespread HPV2-positive warts that completely regressed after administration of tetravalent human papillomavirus vaccine
- Author
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Landini, Manuela Miriam, Borgogna, C, Peretti, A, Doorbar, J, Griffin, H, Mignone, F, Lai, A, Urbinati, L, Matteelli, A, Gariglio, M, and DE ANDREA, Marco
- Subjects
deep sequencing ,vaccine ,papillomavirus, vaccine, deep sequencing, skin virome ,skin virome ,papillomavirus - Published
- 2015
14. The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters. M. DE ANDREA CO-FIRST AUTHOR
- Author
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LO CIGNO, Irene, DE ANDREA, Marco, Borgogna, C., Albertini, S., Landini, Manuela Miriam, Peretti, A., Johnson, K., Chandran, B., Landolfo, Santo Giuseppe, and Gariglio, M.
- Published
- 2015
15. Evidence for human beta-papillomavirus (b-HPV) infection in skin tumours from a cohort of kidney transplant recipients
- Author
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Musetti, C., Borgogna, C., Zavattaro, E., Boldorini, R., Miglio, U., Lanfredini, S., DE ANDREA, Marco, de Koning, M., Stratta, P., Gariglio, M., and Quint, K.
- Published
- 2014
16. IL GENE INTERFERON-INDUCIBILE IFI16: POTENZIALE FATTORE ANTIVIRALE E MARCATORE DIAGNOSTICO DELLE INFEZIONI DA PAPILLOMAVIRUS UMANI
- Author
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Biolatti, Matteo, LO CIGNO, Irene, Landini, M. M., Dell'Oste, Valentina, Borgogna, C., Valeria, Caneparo, Landolfo, Santo Giuseppe, Gariglio, M., and DE ANDREA, Marco
- Published
- 2013
17. Events during the beta-papillomavirus life cycle in EpidermodysplasiaVerruciformis lesions
- Author
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Borgogna, C., Zavattaro, E., DE ANDREA, Marco, Griffin, H. M., Dell'Oste, Valentina, Azzimonti, B., Landini, M. M., Peh, W. L., Pfister, H., Doorbar, J., Landolfo, Santo Giuseppe, and Gariglio, M.
- Published
- 2011
18. Elucidation of natural beta-HPV host interactions in organotypic raft cultures and skin biopsies from Epidermodysplasia verruciformis patients
- Author
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Borgogna, C., Dell'Oste, Valentina, Azzimonti, B., Zavattaro, E., Mondini, M., DE ANDREA, Marco, Rittà, M., Landolfo, Santo Giuseppe, Doorbar, J., and Gariglio, M.
- Published
- 2010
19. The epithelial-mesenchymal transition induced by keratinocyte growth conditions is overcome by E6 and E7 from HPV16, but not HPV8 and HPV38: characterization of global transcription profiles. [*Azzimonti B, *Dell'Oste V, co-first authors]
- Author
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Azzimonti, B, Dell'Oste, Valentina, Borgogna, C, Mondini, M, Gugliesi, Francesca, DE ANDREA, Marco, Chiorino, G, Scatolini, M, Ghimenti, C, Landolfo, Santo Giuseppe, and Gariglio, M.
- Subjects
Keratinocytes ,HPV ,FAD medium ,Epithelial–mesenchymal transition ,Microarray ,Transcriptional profile - Published
- 2009
20. Elucidation of natural beta-HPV-host interactions in organotypic cultures and skin biopsies from Epidermodysplasia verruciformis patients
- Author
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Dell'Oste, Valentina, Azzimonti, B., Zavattaro, E., Borgogna, C., Landini, M. M., Costa, S., Mondini, M., DE ANDREA, Marco, Landolfo, Santo Giuseppe, and Gariglio, M.
- Published
- 2009
21. Corrigendum to 'Interaction between inflammation and angiogenesis during different stages of cervical carcinogenesis' [Gynecol. Oncol. 108 (2008) 112-120] (DOI:10.1016/j.ygyno.2007.08.095)
- Author
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Mazibrada, J, Ritta, M, Mondini, M, De Andrea, M, Azzimonti, B, Borgogna, C, Ciotti, M, Orlandi, A, Surico, N, Chiusa, L, Landolfo, S, and Gariglio, M
- Subjects
erratum ,priority journal ,error ,Settore MED/08 - Anatomia Patologica - Published
- 2008
22. Modulation of UVB-induced pro-inflammatory molecules expression by HPV oncoproteins
- Author
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Azzimonti, B, Dell'Oste, Valentina, Mondini, M, DE ANDREA, Marco, Borgogna, C, Mesturini, R, Accardi, R, Tommasino, M, Dianzani, U, and Gariglio, M.
- Published
- 2007
23. 1003 - Role of polyomavirus BK in the carcinogenesis of urothelial and renal tumours in kidney transplant recipients
- Author
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Poletti, F., Borgogna, C., Billia, M., Zacchero, M., Boldorini, R., Cantaluppi, V., Gariglio, M., and Volpe, A.
- Published
- 2017
- Full Text
- View/download PDF
24. HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses.
- Author
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Morgan HJ, Olivero C, Shorning BY, Gibbs A, Phillips AL, Ananthan L, Lim AXH, Martuscelli L, Borgogna C, De Andrea M, Hufbauer M, Goodwin R, Akgül B, Gariglio M, and Patel GK
- Subjects
- Humans, Animals, Mice, Disease Models, Animal, Female, STAT3 Transcription Factor metabolism, Keratinocytes virology, Keratinocytes metabolism, Keratinocytes pathology, Keratosis, Actinic pathology, Keratosis, Actinic metabolism, Keratosis, Actinic virology, Stem Cells metabolism, Stem Cells virology, Oncogene Proteins, Viral metabolism, Oncogene Proteins, Viral genetics, Papillomavirus Infections virology, Papillomavirus Infections pathology, Papillomavirus Infections metabolism, Papillomavirus Infections complications, Cell Proliferation
- Abstract
Despite epidermal turnover, the skin is host to a complex array of microbes, including viruses, such as HPV, which must infect and manipulate skin keratinocyte stem cells (KSCs) to survive. This crosstalk between the virome and KSC populations remains largely unknown. Here, we investigated the effect of HPV8 on KSCs using various mouse models. We observed that the HPV8 early region gene E6 specifically caused Lrig1+ hair follicle junctional zone KSC proliferation and expansion, which would facilitate viral transmission. Within Lrig1+ KSCs specifically, HPV8 E6 bound intracellular p300 to phosphorylate the STAT3 transcriptional regulatory node. This induced ΔNp63 expression, resulting in KSC expansion into the overlying epidermis. HPV8 was associated with 70% of human actinic keratoses. Together, these results define the "hit-and-run" mechanism for HPV8 in human actinic keratosis as an expansion of KSCs, which lack melanosome protection and are thus susceptible to sun light-induced malignant transformation.
- Published
- 2024
- Full Text
- View/download PDF
25. A prospective humoral immune monitoring study of kidney transplant recipients receiving three doses of SARS-CoV-2 mRNA vaccine.
- Author
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Borgogna C, Ferrante D, Rosso G, Guglielmetti G, Lo Cigno I, Raviola S, Caneparo V, Quaglia M, Cantaluppi V, and Gariglio M
- Subjects
- Humans, Male, Female, Middle Aged, Prospective Studies, Aged, Adult, Immunoglobulin G blood, Monitoring, Immunologic methods, mRNA Vaccines, Spike Glycoprotein, Coronavirus immunology, Longitudinal Studies, Kidney Transplantation adverse effects, Antibodies, Viral blood, Antibodies, Neutralizing blood, COVID-19 prevention & control, COVID-19 immunology, Immunity, Humoral, SARS-CoV-2 immunology, Immunization, Secondary, Transplant Recipients, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage
- Abstract
Kidney transplant recipients (KTRs), like other solid organ transplant recipients display a suboptimal response to mRNA vaccines, with only about half achieving seroconversion after two doses. However, the effectiveness of a booster dose, particularly in generating neutralizing antibodies (NAbs), remains poorly understood, as most studies have mainly focused on non-neutralizing antibodies. Here, we have longitudinally assessed the humoral response to the SARS-CoV-2 mRNA vaccine in 40 KTRs over a year, examining changes in both anti-spike IgG and NAbs following a booster dose administered about 5 months post-second dose. We found a significant humoral response increase 5 months post-booster, a stark contrast to the attenuated response observed after the second dose. Of note, nearly a quarter of participants did not achieve protective plasma levels even after the booster dose. We also found that the higher estimated glomerular filtration rate (eGFR) correlated with a more robust humoral response postvaccination. Altogether, these findings underscore the effectiveness of the booster dose in enhancing durable humoral immunity in KTRs, as evidenced by the protective level of NAbs found in 65% of the patients 5 months post- booster, especially those with higher eGFR rates., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)
- Published
- 2024
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- View/download PDF
26. Longitudinal monitoring of SARS-CoV-2 viral load in self-collected saliva from health care workers during breakthrough infections to spare working days.
- Author
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Caneparo V, Rinaldi C, Ferrante D, Ravanini P, Lo Cigno I, Cavalieri S, Gariglio M, and Borgogna C
- Subjects
- Humans, Breakthrough Infections, Reproducibility of Results, Saliva, Viral Load, Health Personnel, Real-Time Polymerase Chain Reaction, SARS-CoV-2, COVID-19 diagnosis
- Abstract
Importance: Real-time quantitative PCR (RT-qPCR) on nasopharyngeal swabs (NPS) has been used as the standard method for detecting and monitoring SARS-CoV-2 infection during the pandemic. However, NPS collection often causes discomfort and poses a higher risk of transmission to health care workers (HCW). Furthermore, RT-qPCR only provides relative quantification and does not allow distinguishing those samples with residual, no longer active infection, whereas droplet digital PCR (ddPCR) allows for precise quantification of viral load, offering greater sensitivity and reproducibility. This study highlights the effectiveness of using self-collected saliva as a convenient and reliable sampling method. By utilizing ddPCR to measure the SARS-CoV-2 viral load in saliva samples, individuals with low or undetectable viral loads can be quickly identified. This approach is particularly advantageous for surveillance programs targeting HCW, as it enables the early identification and release of uninfected personnel, minimizing lost workdays. Additionally, analyzing viral load in saliva samples by ddPCR is valuable in determining virus shedding duration across different SARS-CoV-2 variants, informing transmission and disease control. Finally, testing saliva could overcome the detection of historic cases due to prolonged RNA swabbing past-infection and the unnecessary exclusion of those individuals from the workplace., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
- Full Text
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27. SIRT1 is an actionable target to restore p53 function in HPV-associated cancer therapy.
- Author
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Lo Cigno I, Calati F, Girone C, Borgogna C, Venuti A, Boldorini R, and Gariglio M
- Subjects
- Humans, Mice, Animals, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Human Papillomavirus Viruses, Sirtuin 1 genetics, Sirtuin 1 metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Mice, Inbred C57BL, Apoptosis, Papillomavirus Infections complications, Papillomavirus Infections drug therapy, Oncogene Proteins, Viral genetics, Neoplasms
- Abstract
Background: Our aim was to evaluate the efficacy and anti-cancer action of a precision medicine approach involving a novel SIRT1-dependent pathway that, when disrupted, leads to the restoration of a functional p53 in human papillomavirus (HPV)-transformed cells., Methods: The anticancer potential of inhibiting SIRT1 was evaluated by examining the effects of the specific SIRT1 inhibitor EX527 (also known as Selisistat) or genetic silencing, either individually or in conjunction with standard chemotherapeutic agents, on a range of HPV
+ cancer cells and a preclinical mouse model of HPV16-induced cancer., Results: We show that SIRT1 inhibition restores a transcriptionally active K382-acetylated p53 in HPV+ but not HPV- cell lines, which in turn promotes G0 /G1 cell cycle arrest and inhibits clonogenicity specifically in HPV+ cells. Additionally, EX527 treatment increases the sensitivity of HPV+ cells to sublethal doses of standard genotoxic agents. The enhanced sensitivity to cisplatin as well as p53 restoration were also observed in an in vivo tumorigenicity assay using syngeneic C3.43 cells harbouring an integrated HPV16 genome, injected subcutaneously into C57BL/6J mice., Conclusions: Our findings uncover an essential role of SIRT1 in HPV-driven oncogenesis, which may have direct translational implications for the treatment of this type of cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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28. The RIG-I agonist M8 triggers cell death and natural killer cell activation in human papillomavirus-associated cancer and potentiates cisplatin cytotoxicity.
- Author
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Girone C, Calati F, Lo Cigno I, Salvi V, Tassinari V, Schioppa T, Borgogna C, Lospinoso Severini L, Hiscott J, Cerboni C, Soriani A, Bosisio D, and Gariglio M
- Subjects
- Female, Humans, Animals, Mice, Human Papillomavirus Viruses, Cisplatin pharmacology, Apoptosis, Killer Cells, Natural, Papillomavirus Infections complications, Neoplasms
- Abstract
Although the activation of innate immunity to treat a wide variety of cancers is gaining increasing attention, it has been poorly investigated in human papillomavirus (HPV)-associated malignancies. Because these tumors harbor a severely impaired cGAS-STING axis, but they still retain a largely functional RIG-I pathway, another critical mediator of adaptive and innate immune responses, we asked whether RIG-I activation by the 5'ppp-RNA RIG-I agonist M8 would represent a therapeutically viable option to treat HPV
+ cancers. Here, we show that M8 transfection of two cervical carcinoma-derived cell lines, CaSki and HeLa, both expressing a functional RIG-I, triggers intrinsic apoptotic cell death, which is significantly reduced in RIG-I KO cells. We also demonstrate that M8 stimulation potentiates cisplatin-mediated cell killing of HPV+ cells in a RIG-I dependent manner. This combination treatment is equally effective in reducing tumor growth in a syngeneic pre-clinical mouse model of HPV16-driven cancer, where enhanced expression of lymphocyte-recruiting chemokines and cytokines correlated with an increased number of activated natural killer (NK) cells in the tumor microenvironment. Consistent with a role of RIG-I signaling in immunogenic cell killing, stimulation of NK cells with conditioned medium from M8-transfected CaSki boosted NK cell proliferation, activation, and migration in a RIG-I-dependent tumor cell-intrinsic manner. Given the highly conserved molecular mechanisms of carcinogenesis and genomic features of HPV-driven cancers and the remarkably improved prognosis for HPV+ oropharyngeal cancer, targeting RIG-I may represent an effective immunotherapeutic strategy in this setting, favoring the development of de-escalating strategies., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
29. Cancer-Associated Fibroblasts Exert Proangiogenic Activity in Merkel Cell Carcinoma.
- Author
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Albertini S, Martuscelli L, Borgogna C, Virdi S, Indenbirken D, Lo Cigno I, Griffante G, Calati F, Boldorini R, Fischer N, and Gariglio M
- Subjects
- Animals, Mice, Humans, Glutamyl Aminopeptidase metabolism, Fibroblasts metabolism, Tumor Microenvironment, Cancer-Associated Fibroblasts metabolism, Carcinoma, Merkel Cell pathology, Skin Neoplasms pathology
- Abstract
The tumor microenvironment is a complex niche enveloping a tumor formed by extracellular matrix, blood vessels, immune cells, and fibroblasts constantly interacting with cancer cells. Although tumor microenvironment is increasingly recognized as a major player in cancer initiation and progression in many tumor types, its involvement in Merkel cell carcinoma (MCC) pathogenesis is currently unknown. In this study, we provide a molecular and functional characterization of cancer-associated fibroblasts (CAFs), the major tumor microenvironment component, in patient-derived xenografts of patients with MCC. We show that subcutaneous coinjection of patient-derived CAFs and human MCC MKL-1 cells into severe combined immunodeficient mice significantly promotes tumor growth and metastasis. These fast-growing xenografts are characterized by areas densely populated with human CAFs, mainly localized around blood vessels. We provide evidence that the growth-promoting activity of MCC-derived CAFs is mediated by the aminopeptidase A/angiotensin II and III/angiotensin II type 1 receptor axis, with the expression of aminopeptidase A in CAFs being a triggering event. Together, our findings point to aminopeptidase A as a potential marker for MCC prognostic stratification and as a candidate for therapeutic intervention., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
30. Enhanced Spontaneous Skin Tumorigenesis and Aberrant Inflammatory Response to UVB Exposure in Immunosuppressed Human Papillomavirus Type 8‒Transgenic Mice.
- Author
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Borgogna C, Martuscelli L, Olivero C, Lo Cigno I, De Andrea M, Caneparo V, Boldorini R, Patel G, and Gariglio M
- Subjects
- Humans, Mice, Animals, Mice, Transgenic, Human Papillomavirus Viruses, Skin pathology, Carcinogenesis pathology, Papillomaviridae genetics, Skin Neoplasms genetics, Skin Neoplasms pathology, Papillomavirus Infections complications
- Abstract
Human papillomaviruses (HPVs) from the beta genus are commensal viruses of the skin usually associated with asymptomatic infection in the general population. However, in individuals with specific genetic backgrounds, such as patients with epidermodysplasia verruciformis, or those with immune defects, such as organ transplant recipients, they are functionally involved in sunlight-induced skin cancer development, mainly keratinocyte carcinoma. Despite their well-established protumorigenic role, the cooperation between β-HPV infection, impaired host immunosurveillance, and UVB exposure has never been formally shown in animal models. In this study, by crossing skin-specific HPV8-transgenic mice with Rag2-deficient mice, we have generated a preclinical mouse model, named Rag2
‒/‒ :K14-HPV8. These mice display an unhealthy skin phenotype and spontaneously develop papilloma-like lesions spreading to the entire skin much more rapidly compared with Rag2+/+ :K14-HPV8 mice. Exposure to low doses of UVB radiation is sufficient to trigger severe skin inflammation in Rag2‒/‒ :K14-HPV8 but not in Rag2+/+ :K14-HPV8 mice. Their inflamed skin very much resembled that observed in cutaneous field cancerization in organ transplant recipients, showing high levels of UVB-damaged cells, enhanced production of proinflammatory cytokines, and mast cell recruitment to the dermis. Overall, this immunocompromised HPV8-transgenic mouse model shows that the coexistence of immune defects, β-HPV, and UVB exposure promotes skin cancer development., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
31. #Stayathome If You Have a Cold: High SARS-CoV-2 Salivary Viral Loads in Pediatric Patients with Nasopharyngeal Symptoms.
- Author
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Monzani A, Borgogna C, Ferrante D, Ciacchini B, Felici E, Gariglio M, and Rabbone I
- Subjects
- Humans, Child, Viral Load, Real-Time Polymerase Chain Reaction, Nasopharynx, Saliva, Specimen Handling, SARS-CoV-2 genetics, COVID-19 diagnosis
- Abstract
The choice of the best SARS-CoV-2 detection approach is crucial to predict which children with SARS-CoV-2 are at high risk of spreading the virus in order to manage public health measures and policies. In this prospective observational study of 35 children admitted to the Pediatric Emergency Departments of two tertiary hospitals in Northern Italy who tested positive for SARS-CoV-2 by standard RT-PCR in nasopharyngeal swab (NPS), we evaluated their presenting symptoms according to their salivary viral load (SVL) determined by droplet digital PCR (ddPCR). Despite an overall low concordance between SARS-CoV-2 detected by salivary ddPCR and NPS RT-PCR (54.3%), when only patients with nasopharyngeal symptoms were analyzed, the sensitivity of ddPCR in saliva specimens increased to 71.4%, and over half of these patients had high SVL (>105 copies/mL), which was significantly more frequent than in children without nasopharyngeal symptoms (57.1% vs. 14.3%, OR = 8, CI 95% 1.28−50.03, p = 0.03). All asymptomatic children had low SVL values. Our findings support the hypothesis that children with nasopharyngeal symptoms are at higher risk of spreading SARS-CoV-2 due to their high SVL and, conversely, asymptomatic children are unlikely to spread the virus due to their low SVL, regardless of their NPS positivity.
- Published
- 2022
- Full Text
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32. Induction of robust humoral immunity against SARS-CoV-2 after vaccine administration in previously infected haematological cancer patients.
- Author
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Borgogna C, Bruna R, Griffante G, Martuscelli L, De Andrea M, Ferrante D, Patriarca A, Mahmoud AM, Ucciero MAM, Gaidano V, Marchetti M, Rapezzi D, Lai M, Pistello M, Ladetto M, Massaia M, Gaidano G, and Gariglio M
- Subjects
- Humans, SARS-CoV-2, Immunity, Humoral, Vaccination, Antibodies, Viral, Immunity, Cellular, COVID-19 prevention & control, Hematologic Neoplasms therapy, Vaccines
- Published
- 2022
- Full Text
- View/download PDF
33. Patterns of neutralizing humoral response to SARS-CoV-2 infection among hematologic malignancy patients reveal a robust immune response in anti-cancer therapy-naive patients.
- Author
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Borgogna C, Bruna R, Griffante G, Martuscelli L, De Andrea M, Ferrante D, Patriarca A, Mahmoud AM, Gaidano V, Marchetti M, Rapezzi D, Lai M, Pistello M, Ladetto M, Massaia M, Gaidano G, and Gariglio M
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Antineoplastic Agents administration & dosage, COVID-19 immunology, Hematologic Neoplasms drug therapy, Hematologic Neoplasms immunology, Immunity, Humoral, SARS-CoV-2 immunology
- Abstract
Understanding antibody-based SARS-CoV-2 immunity in hematologic malignancy (HM) patients following infection is crucial to inform vaccination strategies for this highly vulnerable population. This cross-sectional study documents the anti-SARS-CoV-2 humoral response and serum neutralizing activity in 189 HM patients recovering from a PCR-confirmed infection. The overall seroconversion rate was 85.7%, with the lowest values in patients with lymphoid malignancies or undergoing chemotherapy. Therapy-naive patients in the "watch and wait" status were more likely to seroconvert and display increased anti-s IgG titers. Enhanced serum neutralizing activity was observed in the following SARS-CoV-2-infected HM patient groups: (i) males; (ii) severe COVID-19; and (iii) "watch and wait" or "complete/partial response". The geometric mean (GeoMean) ID50 neutralization titers in patients analyzed before or after 6 months post-infection were 299.1 and 306.3, respectively, indicating that >50% of the patients in either group had a neutralization titer sufficient to provide 50% protection from symptomatic COVID-19. Altogether, our findings suggest that therapy-naive HM patients mount a far more robust immune response to SARS-CoV-2 infection vs. patients receiving anti-cancer treatment, raising the important question as to whether HM patients should be vaccinated before therapy and/or receive vaccine formats capable of better recapitulating the natural infection., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
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34. SARS-CoV-2 reinfection in a cancer patient with a defective neutralizing humoral response.
- Author
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Borgogna C, De Andrea M, Griffante G, Lai A, Bergna A, Galli M, Zehender G, Castello L, Ravanini P, Cattrini C, Mennitto A, Gennari A, and Gariglio M
- Subjects
- COVID-19 immunology, Genome, Viral genetics, Humans, Immunity, Humoral immunology, Male, Middle Aged, Reinfection immunology, Reinfection virology, Respiratory Insufficiency mortality, SARS-CoV-2 genetics, Shock, Septic microbiology, Shock, Septic mortality, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 pathology, Carcinoma, Transitional Cell pathology, Kidney Neoplasms pathology, SARS-CoV-2 immunology
- Published
- 2021
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35. Persistence of Neutralizing Antibodies to SARS-CoV-2 in First Wave Infected Individuals at Ten Months Post-Infection: The UnIRSA Cohort Study.
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Griffante G, Chandel S, Ferrante D, Caneparo V, Capello D, Bettio V, Borgogna C, Aleni C, Esposito S, Sarro A, Vasile A, Comba M, Testa T, Cotrupi G, De Andrea M, Bortoluzzi S, and Gariglio M
- Subjects
- Adult, Asymptomatic Infections, COVID-19 epidemiology, COVID-19 virology, COVID-19 Serological Testing, Cohort Studies, Female, Humans, Immunity, Immunity, Humoral, Immunoglobulin G blood, Italy epidemiology, Longitudinal Studies, Male, Middle Aged, Seroconversion, Vaccine Development, Antibodies, Neutralizing immunology, Antibodies, Viral blood, COVID-19 immunology, COVID-19 Vaccines immunology, Protein Domains immunology, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology
- Abstract
Longitudinal mapping of antibody-based SARS-CoV-2 immunity is critical for public health control of the pandemic and vaccine development. We performed a longitudinal analysis of the antibody-based immune response in a cohort of 100 COVID-19 individuals who were infected during the first wave of infection in northern Italy. The SARS-CoV-2 humoral response was tested using the COVID-SeroIndex, Kantaro Quantitative SARS-CoV-2 IgG Antibody RUO Kit (R&D Systems, Bio-Techne, Minneapolis, USA) and pseudotype-based neutralizing antibody assay. Using sequential serum samples collected from 100 COVID-19 recovered individuals from northern Italy-mostly with mild disease-at 2 and 10 months after their first positive PCR test, we show that 93% of them seroconverted at 2 months, with a geometric mean (GeoMean) half-maximal neutralization titer (NT50) of 387.9. Among the 35 unvaccinated subjects retested at 10 months, 7 resulted seronegative, with an 80% drop in seropositivity, while 28 showed decreased anti-receptor binding domain (RBD) and anti-spike (S) IgG titers, with a GeoMean NT50 neutralization titer dropping to 163.5. As an NT50 > 100 is known to confer protection from SARS-CoV-2 re-infection, our data show that the neutralizing activity elicited by the natural infection has lasted for at least 10 months in a large fraction of subjects.
- Published
- 2021
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36. Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story.
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Quaglia M, Merlotti G, De Andrea M, Borgogna C, and Cantaluppi V
- Subjects
- Antiphospholipid Syndrome immunology, Antiphospholipid Syndrome virology, Autoimmunity immunology, Cytomegalovirus Infections pathology, Endogenous Retroviruses physiology, Epstein-Barr Virus Infections pathology, Herpesvirus 4, Human physiology, Host-Pathogen Interactions physiology, Humans, Lupus Erythematosus, Systemic virology, Parvoviridae Infections pathology, Parvovirus B19, Human physiology, Cytomegalovirus immunology, Endogenous Retroviruses immunology, Herpesvirus 4, Human immunology, Immunity, Innate immunology, Lupus Erythematosus, Systemic immunology, Parvovirus B19, Human immunology
- Abstract
A causal link between viral infections and autoimmunity has been studied for a long time and the role of some viruses in the induction or exacerbation of systemic lupus erythematosus (SLE) in genetically predisposed patients has been proved. The strength of the association between different viral agents and SLE is variable. Epstein-Barr virus (EBV), parvovirus B19 (B19V), and human endogenous retroviruses (HERVs) are involved in SLE pathogenesis, whereas other viruses such as Cytomegalovirus (CMV) probably play a less prominent role. However, the mechanisms of viral-host interactions and the impact of viruses on disease course have yet to be elucidated. In addition to classical mechanisms of viral-triggered autoimmunity, such as molecular mimicry and epitope spreading, there has been a growing appreciation of the role of direct activation of innate response by viral nucleic acids and epigenetic modulation of interferon-related immune response. The latter is especially important for HERVs, which may represent the molecular link between environmental triggers and critical immune genes. Virus-specific proteins modulating interaction with the host immune system have been characterized especially for Epstein-Barr virus and explain immune evasion, persistent infection and self-reactive B-cell "immortalization". Knowledge has also been expanding on key viral proteins of B19-V and CMV and their possible association with specific phenotypes such as antiphospholipid syndrome. This progress may pave the way to new therapeutic perspectives, including the use of known or new antiviral drugs, postviral immune response modulation and innate immunity inhibition. We herein describe the state-of-the-art knowledge on the role of viral infections in SLE, with a focus on their mechanisms of action and potential therapeutic targets.
- Published
- 2021
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37. Evidence of BK Polyomavirus Infection in Urothelial but not Renal Tumors from a Single Center Cohort of Kidney Transplant Recipients.
- Author
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Borgogna C, Albertini S, Martuscelli L, Poletti F, Volpe A, Merlotti G, Cantaluppi V, Boldorini R, and Gariglio M
- Subjects
- Adult, Antigens, Viral, Tumor analysis, Female, Humans, In Situ Hybridization, Fluorescence, Kidney Neoplasms pathology, Male, Middle Aged, Retrospective Studies, Transplant Recipients, Urothelium pathology, BK Virus, Kidney Neoplasms virology, Kidney Transplantation adverse effects, Polyomavirus Infections virology, Urothelium virology
- Abstract
Emerging evidence indicates that reactivation of BK polyomavirus (BKPyV) in the kidney and urothelial tract of kidney transplant recipients (KTRs) may be associated with cancer in these sites. In this retrospective study of a single center cohort of KTRs ( n = 1307), 10 clear cell renal cell carcinomas and 5 urinary bladder carcinomas were analyzed from 15 KTRs for the presence of BKPyV infection through immunohistochemistry and fluorescent in situ hybridization (FISH). Three of these patients had already exhibited biopsy-proven polyomavirus-associated nephropathies (PyVAN). Although the presence of BKPyV large-T antigen was evident in the urothelium from a kidney removed soon after PyVAN diagnosis, it was undetectable in all the formalin-fixed and paraffin-embedded (FFPE) blocks obtained from the 10 kidney tumors. By contrast, large-T antigen (LT) labeling of tumor cells was detected in two out of five bladder carcinomas. Lastly, the proportion of BKPyV DNA-FISH-positive bladder carcinoma nuclei was much lower than that of LT-positive cells. Taken together, our findings further strengthen the association between BKPyV reactivation and cancer development in KTRs, especially bladder carcinoma.
- Published
- 2021
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38. Human Papillomavirus E7 Oncoprotein Subverts Host Innate Immunity via SUV39H1-Mediated Epigenetic Silencing of Immune Sensor Genes.
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Lo Cigno I, Calati F, Borgogna C, Zevini A, Albertini S, Martuscelli L, De Andrea M, Hiscott J, Landolfo S, and Gariglio M
- Subjects
- Cell Line, DEAD Box Protein 58 metabolism, Epigenesis, Genetic genetics, HEK293 Cells, HeLa Cells, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Immune Evasion genetics, Immune Evasion immunology, Immunity, Innate genetics, Immunity, Innate immunology, Interferon-beta metabolism, Keratinocytes virology, Membrane Proteins metabolism, Methyltransferases genetics, Nucleotidyltransferases metabolism, Oncogene Proteins, Viral metabolism, Papillomaviridae pathogenicity, Papillomavirus E7 Proteins physiology, Papillomavirus Infections virology, Receptors, Immunologic, Repressor Proteins genetics, Signal Transduction genetics, Transcriptional Activation genetics, Methyltransferases metabolism, Papillomaviridae metabolism, Papillomavirus E7 Proteins metabolism, Repressor Proteins metabolism
- Abstract
Subversion of innate immunity by oncoviruses, such as human papillomavirus (HPV), favors carcinogenesis because the mechanism(s) of viral immune evasion can also hamper cancer immunosurveillance. Previously, we demonstrated that high-risk (hr) HPVs trigger simultaneous epigenetic silencing of multiple effectors of innate immunity to promote viral persistence. Here, we expand on those observations and show that the HPV E7 oncoprotein upregulates the H3K9-specific methyltransferase, whose action shuts down the host innate immune response. Specifically, we demonstrate that SUV39H1 contributes to chromatin repression at the promoter regions of the viral nucleic acid sensors RIG-I and cGAS and the adaptor molecule STING in HPV-transformed cells. Inhibition of SUV39H1 leads to transcriptional activation of these genes, especially RIG-I, followed by increased beta interferon (IFN-β) and IFN-λ
1 production after poly(dA·dT) or RIG-I agonist M8 transfection. Collectively, our findings provide new evidence that the E7 oncoprotein plays a central role in dampening host innate immunity and raise the possibility that targeting the downstream effector SUV39H1 or the RIG-I pathway is a viable strategy to treat viral and neoplastic disease. IMPORTANCE High-risk HPVs are major viral human carcinogens responsible for approximately 5% of all human cancers. The growth of HPV-transformed cells depends on the ability of viral oncoproteins to manipulate a variety of cellular circuits, including those involved in innate immunity. Here, we show that one of these strategies relies on E7-mediated transcriptional activation of the chromatin repressor SUV39H1, which then promotes epigenetic silencing of RIG-I, cGAS, and STING genes, thereby shutting down interferon secretion in HPV-transformed cells. Pharmacological or genetic inhibition of SUV39H1 restored the innate response in HPV-transformed cells, mostly through activation of RIG-I signaling. We also show that IFN production upon transfection of poly(dA·dT) or the RIG-I agonist M8 predominantly occurs through RIG-I signaling. Altogether, the reversible nature of the modifications associated with E7-mediated SUV39H1 upregulation provides a rationale for the design of novel anticancer and antiviral therapies targeting these molecules., (Copyright © 2020 American Society for Microbiology.)- Published
- 2020
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39. Primary trichodysplasia spinulosa polyomavirus infection in a kidney transplant child displaying virus-infected decoy cells in the urine.
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Borgogna C, Albertini S, Zavattaro E, Veronese F, Peruzzi L, van der Meijden E, Feltkamp MCW, Tosoni A, Volpe A, Boldorini R, and Gariglio M
- Subjects
- Child, Humans, Immunocompromised Host, Male, Polyomavirus classification, Epithelial Cells virology, Kidney Transplantation, Polyomavirus isolation & purification, Polyomavirus Infections urine, Polyomavirus Infections virology, Transplant Recipients
- Abstract
We report a case of primary trichodysplasia spinulosa (TS) infection in a kidney transplant child and describe for the first time the presence of degenerated TS-associated polyomavirus (TSPyV)-infected cells in a TS patient's urine that are morphologically different from BK or JC polyomavirus-infected decoy cells., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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40. Metagenomic Discovery of 83 New Human Papillomavirus Types in Patients with Immunodeficiency.
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Pastrana DV, Peretti A, Welch NL, Borgogna C, Olivero C, Badolato R, Notarangelo LD, Gariglio M, FitzGerald PC, McIntosh CE, Reeves J, Starrett GJ, Bliskovsky V, Velez D, Brownell I, Yarchoan R, Wyvill KM, Uldrick TS, Maldarelli F, Lisco A, Sereti I, Gonzalez CM, Androphy EJ, McBride AA, Van Doorslaer K, Garcia F, Dvoretzky I, Liu JS, Han J, Murphy PM, McDermott DH, and Buck CB
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, DNA, Viral chemistry, Female, Genome, Viral, High-Throughput Nucleotide Sequencing, Humans, Male, Metagenomics, Middle Aged, Mucous Membrane virology, Nucleic Acid Amplification Techniques, Papillomaviridae genetics, Skin virology, Young Adult, DNA, Viral genetics, Immunologic Deficiency Syndromes complications, Papillomaviridae classification, Papillomaviridae isolation & purification, Papillomavirus Infections virology
- Abstract
Several immunodeficiencies are associated with high susceptibility to persistent and progressive human papillomavirus (HPV) infection leading to a wide range of cutaneous and mucosal lesions. However, the HPV types most commonly associated with such clinical manifestations in these patients have not been systematically defined. Here, we used virion enrichment, rolling circle amplification, and deep sequencing to identify circular DNA viruses present in skin swabs and/or wart biopsy samples from 48 patients with rare genetic immunodeficiencies, including patients with warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, or epidermodysplasia verruciformis (EV). Their profiles were compared with the profiles of swabs from 14 healthy adults and warts from 6 immunologically normal children. Individual patients were typically infected with multiple HPV types; up to 26 different types were isolated from a single patient (multiple anatomical sites, one time point). Among these, we identified the complete genomes of 83 previously unknown HPV types and 35 incomplete genomes representing possible additional new types. HPV types in the genus Gammapapillomavirus were common in WHIM patients, whereas EV patients mainly shed HPVs from the genus Betapapillomavirus. Preliminary evidence based on three WHIM patients treated with plerixafor, a leukocyte mobilizing agent, suggest that longer-term therapy may correlate with decreased HPV diversity and increased predominance of HPV types associated with childhood skin warts. IMPORTANCE Although some members of the viral family Papillomaviridae cause benign skin warts (papillomas), many human papillomavirus (HPV) infections are not associated with visible symptoms. For example, most healthy adults chronically shed Gammapapillomavirus ( Gamma ) virions from apparently healthy skin surfaces. To further explore the diversity of papillomaviruses, we performed viromic surveys on immunodeficient individuals suffering from florid skin warts. Our results nearly double the number of known Gamma HPV types and suggest that WHIM syndrome patients are uniquely susceptible to Gamma HPV-associated skin warts. Preliminary results suggest that treatment with the drug plerixafor may promote resolution of the unusual Gamma HPV skin warts observed in WHIM patients.
- Published
- 2018
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41. Characterization of BK Polyomaviruses from Kidney Transplant Recipients Suggests a Role for APOBEC3 in Driving In-Host Virus Evolution.
- Author
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Peretti A, Geoghegan EM, Pastrana DV, Smola S, Feld P, Sauter M, Lohse S, Ramesh M, Lim ES, Wang D, Borgogna C, FitzGerald PC, Bliskovsky V, Starrett GJ, Law EK, Harris RS, Killian JK, Zhu J, Pineda M, Meltzer PS, Boldorini R, Gariglio M, and Buck CB
- Subjects
- APOBEC Deaminases, Adult, Amino Acid Substitution, Animals, Antibodies, Neutralizing, Antibodies, Viral, BK Virus immunology, Capsid Proteins genetics, Cell Line, Chromosome Mapping, Cytidine Deaminase, DNA Damage, DNA, Viral analysis, DNA, Viral genetics, Female, HEK293 Cells, Humans, Italy, Kidney Diseases pathology, Kidney Diseases virology, Male, Middle Aged, Mutation, Polyomavirus Infections blood, Polyomavirus Infections immunology, Polyomavirus Infections pathology, Tumor Virus Infections blood, Tumor Virus Infections immunology, Tumor Virus Infections pathology, BK Virus genetics, Cytosine Deaminase physiology, Kidney Transplantation, Polyomavirus Infections virology, Tumor Virus Infections virology
- Abstract
BK polyomavirus (BKV) frequently causes nephropathy (BKVN) in kidney transplant recipients (KTRs). BKV has also been implicated in the etiology of bladder and kidney cancers. We characterized BKV variants from two KTRs who developed BKVN followed by renal carcinoma. Both patients showed a swarm of BKV sequence variants encoding non-silent mutations in surface loops of the viral major capsid protein. The temporal appearance and disappearance of these mutations highlights the intra-patient evolution of BKV. Some of the observed mutations conferred resistance to antibody-mediated neutralization. The mutations also modified the spectrum of receptor glycans engaged by BKV during host cell entry. Intriguingly, all observed mutations were consistent with DNA damage caused by antiviral APOBEC3 cytosine deaminases. Moreover, APOBEC3 expression was evident upon immunohistochemical analysis of renal biopsies from KTRs. These results provide a snapshot of in-host BKV evolution and suggest that APOBEC3 may drive BKV mutagenesis in vivo., (Published by Elsevier Inc.)
- Published
- 2018
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42. HPV-Induced Field Cancerisation: Transformation of Adult Tissue Stem Cell Into Cancer Stem Cell.
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Olivero C, Lanfredini S, Borgogna C, Gariglio M, and Patel GK
- Abstract
Field cancerisation was originally described as a basis for multiple head and neck squamous cell carcinoma (HNSCC) and is a pre-malignant phenomenon that is frequently attributable to oncogenic human papillomavirus (HPV) infection. Our work on β-HPV-induced cutaneous squamous cell carcinomas identified a novel Lrig1+ hair follicle junctional zone keratinocyte stem cell population as the basis for field cancerisation. Herein, we describe the ability for HPV to infect adult tissue stem cells in order to establish persistent infection and induce their proliferation and displacement resulting in field cancerisation. By review of the HPV literature, we reveal how this mechanism is conserved as the basis of field cancerisation across many tissues. New insights have identified the capacity for HPV early region genes to dysregulate adult tissue stem cell self-renewal pathways ensuring that the expanded population preserve its stem cell characteristics beyond the stem cell niche. HPV-infected cells acquire additional transforming mutations that can give rise to intraepithelial neoplasia (IEN), from environmental factors such as sunlight or tobacco induced mutations in skin and oral cavity, respectively. With establishment of IEN, HPV viral replication is sacrificed with loss of the episome, and the tissue is predisposed to multiple cancer stem cell-driven carcinomas.
- Published
- 2018
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43. HPV18 Persistence Impairs Basal and DNA Ligand-Mediated IFN-β and IFN-λ 1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling.
- Author
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Albertini S, Lo Cigno I, Calati F, De Andrea M, Borgogna C, Dell'Oste V, Landolfo S, and Gariglio M
- Subjects
- 3T3 Cells, Animals, Cell Line, Cell Line, Tumor, Down-Regulation genetics, Gene Expression Regulation, Viral genetics, HeLa Cells, Host-Pathogen Interactions genetics, Humans, Immunity, Innate genetics, Keratinocytes virology, Ligands, Mice, DNA genetics, Human papillomavirus 18 genetics, Interferon-beta genetics, Receptors, Pattern Recognition genetics, Signal Transduction genetics, Transcription, Genetic genetics
- Abstract
Although it is clear that high-risk human papillomaviruses (HPVs) can selectively infect keratinocytes and persist in the host, it still remains to be unequivocally determined whether they can escape antiviral innate immunity by interfering with pattern recognition receptor (PRR) signaling. In this study, we have assessed the innate immune response in monolayer and organotypic raft cultures of NIKS cells harboring multiple copies of episomal HPV18 (NIKSmcHPV18), which fully recapitulates the persistent state of infection. We show for the first time, to our knowledge, that NIKSmcHPV18, as well as HeLa cells (a cervical carcinoma-derived cell line harboring integrated HPV18 DNA), display marked downregulation of several PRRs, as well as other PRR downstream effectors, such as the adaptor protein stimulator of IFN genes and the transcription factors IRF1 and 7. Importantly, we provide evidence that downregulation of stimulator of IFN genes, cyclic GMP-AMP synthase, and retinoic acid-inducible gene I mRNA levels occurs at the transcriptional level through a novel epigenetic silencing mechanism, as documented by the accumulation of repressive heterochromatin markers seen at the promoter region of these genes. Furthermore, stimulation of NIKSmcHPV18 cells with salmon sperm DNA or poly(deoxyadenylic-deoxythymidylic) acid, two potent inducers of PRR signaling, only partially restored PRR protein expression. Accordingly, the production of IFN-β and IFN-λ
1 was significantly reduced in comparison with the parental NIKS cells, indicating that HPV18 exerts its immunosuppressive activity through downregulation of PRR signaling. Altogether, our findings indicate that high-risk human papillomaviruses have evolved broad-spectrum mechanisms that allow simultaneous depletion of multiple effectors of the innate immunity network, thereby creating an unreactive cellular milieu suitable for viral persistence., (Copyright © 2018 by The American Association of Immunologists, Inc.)- Published
- 2018
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44. Human Cytomegalovirus Tegument Protein pp65 (pUL83) Dampens Type I Interferon Production by Inactivating the DNA Sensor cGAS without Affecting STING.
- Author
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Biolatti M, Dell'Oste V, Pautasso S, Gugliesi F, von Einem J, Krapp C, Jakobsen MR, Borgogna C, Gariglio M, De Andrea M, and Landolfo S
- Subjects
- Cytomegalovirus genetics, Cytomegalovirus Infections genetics, Cytomegalovirus Infections pathology, HEK293 Cells, Humans, Immune Evasion genetics, Immunity, Innate genetics, Interferon Type I genetics, Membrane Proteins genetics, Nucleotidyltransferases genetics, Phosphoproteins genetics, Protein Binding, Signal Transduction genetics, Viral Matrix Proteins genetics, Cytomegalovirus immunology, Cytomegalovirus Infections immunology, Immune Evasion immunology, Interferon Type I immunology, Membrane Proteins immunology, Nucleotidyltransferases immunology, Phosphoproteins immunology, Signal Transduction immunology, Viral Matrix Proteins immunology
- Abstract
The innate immune response plays a pivotal role during human cytomegalovirus (HCMV) primary infection. Indeed, HCMV infection of primary fibroblasts rapidly triggers strong induction of type I interferons (IFN-I), accompanied by proinflammatory cytokine release. Here, we show that primary human foreskin fibroblasts (HFFs) infected with a mutant HCMV TB40/E strain unable to express UL83-encoded pp65 (v65Stop) produce significantly higher IFN-β levels than HFFs infected with the wild-type TB40/E strain or the pp65 revertant (v65Rev), suggesting that the tegument protein pp65 may dampen IFN-β production. To clarify the mechanisms through which pp65 inhibits IFN-β production, we analyzed the activation of the cGAS/STING/IRF3 axis in HFFs infected with either the wild type, the revertant v65Rev, or the pp65-deficient mutant v65Stop. We found that pp65 selectively binds to cGAS and prevents its interaction with STING, thus inactivating the signaling pathway through the cGAS/STING/IRF3 axis. Consistently, addition of exogenous cGAMP to v65Rev-infected cells triggered the production of IFN-β levels similar to those observed with v65Stop-infected cells, confirming that pp65 inactivation of IFN-β production occurs at the cGAS level. Notably, within the first 24 h of HCMV infection, STING undergoes proteasome degradation independently of the presence or absence of pp65. Collectively, our data provide mechanistic insights into the interplay between HCMV pp65 and cGAS, leading to subsequent immune evasion by this prominent DNA virus. IMPORTANCE Primary human foreskin fibroblasts (HFFs) produce type I IFN (IFN-I) when infected with HCMV. However, we observed significantly higher IFN-β levels when HFFs were infected with HCMV that was unable to express UL83-encoded pp65 (v65Stop), suggesting that pp65 (pUL83) may constitute a viral evasion factor. This study demonstrates that the HCMV tegument protein pp65 inhibits IFN-β production by binding and inactivating cGAS early during infection. In addition, this inhibitory activity specifically targets cGAS, since it can be bypassed via the addition of exogenous cGAMP, even in the presence of pp65. Notably, STING proteasome-mediated degradation was observed in both the presence and absence of pp65. Collectively, our data underscore the important role of the tegument protein pp65 as a critical molecular hub in HCMV's evasion strategy against the innate immune response., (Copyright © 2018 American Society for Microbiology.)
- Published
- 2018
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45. β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort.
- Author
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Borgogna C, Olivero C, Lanfredini S, Calati F, De Andrea M, Zavattaro E, Savoia P, Trisolini E, Boldorini R, Patel GK, and Gariglio M
- Abstract
Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been associated with skin infection by human papillomavirus (HPV) from the beta genus. In this report, we extend our previous investigation aimed at identifying the presence of active β-HPV infection in skin tumors from KTRs through detection of viral protein expression. Using a combination of antibodies raised against the E4 and L1 proteins of the β-genotypes, we were able to visualize infection in five tumors [one keratoacanthoma (KA), three actinic keratoses (AKs), and one seborrheic keratoses (SKs)] that were all removed from two patients who had been both transplanted twice, had developed multiple KCs, and presented with a long history of immunosuppression (>30 years). These infected tissues displayed intraepidermal hyperplasia and increased expression of the ΔNp63 protein, which extended into the upper epithelial layers. In addition, using a xenograft model system in nude mice displaying a humanized stromal bed in the site of grafting, we successfully engrafted three AKs, two of which were derived from the aforementioned KTRs and displayed β-HPV infection in the original tumor. Of note, one AK-derived xenograft, along with its ensuing lymph node metastasis, was diagnosed as squamous cell carcinoma (SCC). In the latter, both β-HPV infection and ΔNp63 expression were no longer detectable. Although the overall success rate of engrafting was very low, the results of this study show for the first time that β-HPV
+ and ΔNp63+ intraepidermal hyperplasia can indeed progress to an aggressive SCC able to metastasize. Consistent with a series of reports attributing a causative role of β-HPV at early stages of skin carcinogenesis through ΔNp63 induction and increased keratinocytes stemness, here we provide in vivo evidence that these events are also occurring in the affected skin of KTRs. Due to these β-HPV-driven molecular pathways, the nascent tumor cell is able to acquire a high enough number of carcinogenic insults that its proliferation and survival will eventually become independent of viral gene expression.- Published
- 2018
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46. HPV8 Field Cancerization in a Transgenic Mouse Model Is due to Lrig1+ Keratinocyte Stem Cell Expansion.
- Author
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Lanfredini S, Olivero C, Borgogna C, Calati F, Powell K, Davies KJ, De Andrea M, Harries S, Tang HKC, Pfister H, Gariglio M, and Patel GK
- Subjects
- Animals, Cell Proliferation, Keratinocytes metabolism, Keratosis, Actinic metabolism, Mice, Mice, Transgenic, Neoplastic Stem Cells metabolism, Papillomaviridae, Skin Neoplasms metabolism, Keratinocytes pathology, Keratosis, Actinic pathology, Membrane Glycoproteins metabolism, Neoplasms, Experimental, Neoplastic Stem Cells pathology, Nerve Tissue Proteins metabolism, Skin Neoplasms pathology
- Abstract
β-Human papillomaviruses (HPVs) cause near ubiquitous latent skin infection within long-lived hair follicle (HF) keratinocyte stem cells. In patients with epidermodysplasia verruciformis, β-HPV viral replication is associated with skin keratosis and cutaneous squamous cell carcinoma. To determine the role of HF keratinocyte stem cells in β-HPV-induced skin carcinogenesis, we utilized a transgenic mouse model in which the keratin 14 promoter drives expression of the entire HPV8 early region (HPV8tg). HPV8tg mice developed thicker skin in comparison with wild-type littermates consistent with a hyperproliferative epidermis. HF keratinocyte proliferation was evident within the Lrig1+ keratinocyte stem cell population (69 vs. 55%, P < 0.01, n = 7), and not in the CD34+, LGR5+, and LGR6+ keratinocyte stem cell populations. This was associated with a 2.8-fold expansion in Lrig1+ keratinocytes and 3.8-fold increased colony-forming efficiency. Consistent with this, we observed nuclear p63 expression throughout this population and the HF infundibulum and adjoining interfollicular epidermis, associated with a switch from p63 transcriptional activation isoforms to ΔNp63 isoforms in HPV8tg skin. Epidermodysplasia verruciformis keratosis and in some cases actinic keratoses demonstrated similar histology associated with β-HPV reactivation and nuclear p63 expression within the HF infundibulum and perifollicular epidermis. These findings would suggest that β-HPV field cancerization arises from the HF junctional zone and predispose to squamous cell carcinoma., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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47. The Nuclear DNA Sensor IFI16 Acts as a Restriction Factor for Human Papillomavirus Replication through Epigenetic Modifications of the Viral Promoters.
- Author
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Lo Cigno I, De Andrea M, Borgogna C, Albertini S, Landini MM, Peretti A, Johnson KE, Chandran B, Landolfo S, and Gariglio M
- Subjects
- Cell Nucleus genetics, Down-Regulation, Epigenesis, Genetic, Gene Expression Regulation, Viral, Host-Pathogen Interactions, Human papillomavirus 18 physiology, Humans, Nuclear Proteins genetics, Papillomavirus Infections genetics, Papillomavirus Infections virology, Phosphoproteins genetics, Cell Nucleus metabolism, Human papillomavirus 18 genetics, Nuclear Proteins metabolism, Papillomavirus Infections metabolism, Phosphoproteins metabolism, Promoter Regions, Genetic, Virus Replication
- Abstract
Unlabelled: The human interferon-inducible IFI16 protein, an innate immune sensor of intracellular DNA, was recently demonstrated to act as a restriction factor for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1) infection by inhibiting both viral-DNA replication and transcription. Through the use of two distinct cellular models, this study provides strong evidence in support of the notion that IFI16 can also restrict human papillomavirus 18 (HPV18) replication. In the first model, an immortalized keratinocyte cell line (NIKS) was used, in which the IFI16 protein was knocked down through the use of small interfering RNA (siRNA) technology and overexpressed following transduction with the adenovirus IFI16 (AdVIFI16) vector. The second model consisted of U2OS cells transfected by electroporation with HPV18 minicircles. In differentiated IFI16-silenced NIKS-HPV18 cells, viral-load values were significantly increased compared with differentiated control cells. Consistent with this, IFI16 overexpression severely impaired HPV18 replication in both NIKS and U2OS cells, thus confirming its antiviral restriction activity. In addition to the inhibition of viral replication, IFI16 was also able to reduce viral transcription, as demonstrated by viral-gene expression analysis in U2OS cells carrying episomal HPV18 minicircles and HeLa cells. We also provide evidence that IFI16 promotes the addition of heterochromatin marks and the reduction of euchromatin marks on viral chromatin at both early and late promoters, thus reducing both viral replication and transcription. Altogether, these results argue that IFI16 restricts chromatinized HPV DNA through epigenetic modifications and plays a broad surveillance role against viral DNA in the nucleus that is not restricted to herpesviruses., Importance: Intrinsic immunity is mediated by cellular restriction factors that are constitutively expressed and active even before a pathogen enters the cell. The host nuclear factor IFI16 acts as a sensor of foreign DNA and an antiviral restriction factor, as recently demonstrated by our group for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1). Here, we provide the first evidence that IFI16 inhibits HPV18 replication by repressing viral-gene expression and replication. This antiviral restriction activity was observed in immortalized keratinocytes transfected with the religated genomes and in U2OS cells transfected with HPV18 minicircles, suggesting that it is not cell type specific. We also show that IFI16 promotes the assembly of heterochromatin on HPV DNA. These changes in viral chromatin structure lead to the generation of a repressive state at both early and late HPV18 promoters, thus implicating the protein in the epigenetic regulation of HPV gene expression and replication., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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48. Human Beta-papillomavirus infection and keratinocyte carcinomas.
- Author
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Quint KD, Genders RE, de Koning MN, Borgogna C, Gariglio M, Bouwes Bavinck JN, Doorbar J, and Feltkamp MC
- Subjects
- Animals, Betapapillomavirus immunology, Carcinoma immunology, Carcinoma pathology, Host-Pathogen Interactions, Humans, Keratinocytes immunology, Keratinocytes pathology, Keratinocytes radiation effects, Papillomavirus Infections complications, Papillomavirus Infections immunology, Papillomavirus Infections pathology, Risk Factors, Skin Neoplasms immunology, Skin Neoplasms pathology, Virulence, Betapapillomavirus pathogenicity, Carcinoma virology, Keratinocytes virology, Papillomavirus Infections virology, Skin Neoplasms virology
- Abstract
Although the role of oncogenic human Alpha-papillomaviruses (HPVs) in the development of mucosal carcinomas at different body sites (eg cervix, anus, oropharynx) is fully recognized, a role for HPV in keratinocyte carcinomas (KCs; basal and squamous cell carcinomas) of the skin is not yet clear. KCs are the most common cancers in Caucasians, with the major risk factor being ultraviolet (UV) light exposure. A possible role for Beta-HPV types (BetaPV) in the development of KC was suggested several decades ago, supported by a number of epidemiological studies. Our current review summarizes the recent molecular and histopathological evidence in support of a causal association between BetaPV and the development of KC, and outlines the suspected synergistic effect of viral gene expression with UV radiation and immune suppression. Further insights into the molecular pathways and protein interactions used by BetaPV and the host cell is likely to extend our understanding of the role of BetaPV in KC., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2015
- Full Text
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49. Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients.
- Author
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Borgogna C, Lanfredini S, Peretti A, De Andrea M, Zavattaro E, Colombo E, Quaglia M, Boldorini R, Miglio U, Doorbar J, Bavinck JN, Quint KD, de Koning MN, Landolfo S, and Gariglio M
- Subjects
- Aged, Betapapillomavirus chemistry, Betapapillomavirus genetics, Betapapillomavirus growth & development, Biomarkers, Tumor analysis, Capsid Proteins analysis, Carcinoma, Basal Cell chemistry, Carcinoma, Basal Cell pathology, Carcinoma, Squamous Cell chemistry, Carcinoma, Squamous Cell pathology, Female, Hospitals, University, Humans, Immunohistochemistry, Italy, Keratosis, Actinic metabolism, Keratosis, Actinic pathology, Male, Middle Aged, Minichromosome Maintenance Complex Component 7 analysis, Oncogene Proteins, Viral analysis, Papillomavirus Infections pathology, Polymerase Chain Reaction, Predictive Value of Tests, Risk Factors, Skin Neoplasms chemistry, Skin Neoplasms pathology, Virus Replication, Betapapillomavirus isolation & purification, Carcinoma, Basal Cell virology, Carcinoma, Squamous Cell virology, DNA, Viral isolation & purification, Human Papillomavirus DNA Tests, Keratosis, Actinic virology, Kidney Transplantation adverse effects, Papillomavirus Infections virology, Skin Neoplasms virology
- Abstract
The aim of this study was to determine whether detection of β-HPV gene products, as defined in epidermodysplasia verruciformis skin cancer, could also be observed in lesions from kidney transplant recipients alongside the viral DNA. A total of 111 samples, corresponding to 79 skin lesions abscised from 17 kidney transplant recipients, have been analyzed. The initial PCR analysis demonstrated that β-HPV-DNA was highly present in our tumor series (85%). Using a combination of antibodies raised against the E4 and L1 proteins of the β-genotypes, we were able to visualize productive infection in 4 out of 19 actinic keratoses, and in the pathological borders of 1 out of 14 squamous cell carcinomas and 1 out of 31 basal cell carcinomas. Increased expression of the cellular proliferation marker minichromosome maintenance protein 7 (MCM7), that extended into the upper epithelial layers, was a common feature of all the E4-positive areas, indicating that cells were driven into the cell cycle in areas of productive viral infections. Although the present study does not directly demonstrate a causal role of these viruses, the detection of E4 and L1 positivity in actinic keratosis and the adjacent pathological epithelium of skin cancer, clearly shows that β-HPV are actively replicating in the intraepidermal precursor lesions of kidney transplant recipients and can therefore cooperate with other carcinogenic agents, such as UVB, favoring skin cancer promotion.
- Published
- 2014
- Full Text
- View/download PDF
50. α- and β-papillomavirus infection in a young patient with an unclassified primary T-cell immunodeficiency and multiple mucosal and cutaneous lesions.
- Author
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Landini MM, Borgogna C, Peretti A, Colombo E, Zavattaro E, Boldorini R, Miglio U, Doorbar J, Ravanini P, Kumar R, Moratto D, Badolato R, De Andrea M, and Gariglio M
- Subjects
- Adult, Alphapapillomavirus classification, Alphapapillomavirus genetics, Betapapillomavirus genetics, Betapapillomavirus isolation & purification, DNA, Viral analysis, Flow Cytometry, Genotype, Hair virology, Humans, Immunologic Deficiency Syndromes virology, Lymphopenia immunology, Male, Mucous Membrane virology, Papillomavirus Infections complications, Papillomavirus Infections diagnosis, Papillomavirus Infections virology, Primary Immunodeficiency Diseases, Real-Time Polymerase Chain Reaction, Condylomata Acuminata virology, Immunologic Deficiency Syndromes complications, Papillomavirus Infections pathology
- Abstract
Background: Correlating human papillomavirus (HPV) type with the clinical and histopathological features of skin lesions (from genital and nongenital sites) can present a diagnostic challenge., Objective: In this study, HPV infection patterns were correlated with pathology and clinical presentation in lesional and nonlesional body sites from a young patient with a primary T-cell immunodeficiency., Methods: HPV infection was evaluated at both DNA and protein levels by polymerase chain reaction and immunohistochemistry., Results: The patient's genital lesions were caused exclusively by α-genotypes (high-risk type HPV-51 in the anal and low-risk type HPV-72 in the penile condylomas). The opposite was true for the skin lesions, which were infected by β-genotypes alone (HPV-8 and HPV-24). HPV-24 was the predominant type in terms of viral load, and the only one found in productive areas of infection. The patient had already developed high-grade dysplasia in the anal condyloma-like lesions, and showed areas of early-stage dysplasia in the lesions caused by the β-genotype HPV-24., Limitations: The basic origin of the immunodeficiency is not yet defined., Conclusion: These findings provide proof of principle that both α- and β-genotypes can cause overt dysplastic lesions when immunosurveillance is lost, which is not restricted to epidermodysplasia verruciformis., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
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