MIRKO SCORDIO

Dottore di ricerca

ciclo: XXXV


supervisore: Guido Antonelli

Titolo della tesi: Determination of Interferon related genes controlling papillomavirus replication in vitro and mediating ex vivo anti-papillomavirus response

Introduction More than 5% of all cancers are attributable to HPV infections. Despite the well-established antiviral and antiproliferative activity of the innate immune system, especially type I and III IFNs, as well as NK cells, the evasion mechanism employed by HPV may support the progression of anogenital cancer, mostly in HIV-1 infected MSM, due to sexual behavior and HIV-1 related immunosuppression, which reduces the ability to control the oncogenic processes of HPV. To date, our understanding of the early stages of HPV infection are limited by difficulties in identifying incident HPV infections. In this context, the MmuPV1 mouse model has provided new insights into how the early host response can control PV replication. We hypothesized that HPV, through evasion strategies adopted to overcome the host immune defense, might modulate levels of IFN-pathway related genes, as well as NK cells. In the light of these consideration, my PhD project planned i) to evaluate the gene expression level of specific TLRs and ISGs in anal cells of HIV-1 positive MSM patients, ii) to analyze the frequencies of NK cell subsets in anal biopsies obtained from a subgroup of HIV-1 infected MSM with dysplasia, iii) to measure in vitro the expression levels of selected ISGs in MPEK-BL6 cells infected with MmuPV1. Materials and Methods HIV-1 infected MSM (n=159) underwent anal canal brushing at baseline and follow up (n=45) during routine proctology visit, to allow HPV-DNA detection by PCR and genotyping by sequencing, and analysis of TLRs (TLR2, TLR3, TLR4, TLR8 and TLR9) and ISGs (ISG15, ISG56, MXA, PKR) gene expression by RT/Real time PCR assay. Anal biopsies from abnormal areas and normal mucosa were obtained from a subgroup of HPV-HIV-1 coinfected MSM (n=18), in order to evaluate any differences in the frequencies of CD56+, CD56dim, CD56bright and NKT cells by flow cytometric analysis. MmuPV1 infected-MPEK-BL6 cells were cultured over 144 hours, and early and late viral gene expression, as well as transcription of cellular genes coding for ISGs (STAT1, DDX58, IFIH1, ISG15, HERC6, IFI27, IFI35, IRF7, OAS1, OAS3, OASL1, PLSCR1, SP100, BST2, and SP100), were quantified at serial timepoints by RT/Real time PCR assay. Results Prevalence of patients tested positive for HPV DNA was 71.07%, with HPV6 and HPV16 as the most common genotypes. Patients who resolved and mantained the infection at the follow-up were 13.33% and 86.67%, respectively. Results showed a decreased expression of TLR9 in HPV positive samples compared to negative ones (p=0.021), especially in Lr infections (p=0.004), while no differential expression of the ISGs was recorded. TLR4 and TLR9 transcripts were higher in persistent Hr HPV infections (p=0.041 and p=0.033, respectively), whereas MXA was more activated during low-risks (p=0.0079). A difference in the expression of TLR3 (p=0.046) and TLR8 (p=0.028) was detected among Hr HPV-HIV-1+ positive, compared HIV-1 negative individuals, as well as for ISG15 (p=0.0180) and PKR (p=0.0443). Patients with dysplastic and normal mucosa showed similar levels of the CD56+, CD56dim, and NKT cells; moreover, a significant downregulation of CD56bright in LSIL was caused by Hr HPV. Finally, persistence and cleared infections did not revealed differential frequencies. Compared to undetectable levels of MmuPV1 transcripts in the control cells, in infected MPEK-BL6 we detected ~50.000 copies/µg of early transcripts between 24-72 hours post infection (p.i.), which was then suppressed to ~2.000 copies/µg at later time points. Compared to IFNα induced upregulation of ISGs, the expression of IFIH1, ISG15, OAS1, OASL1 and SP100 unchanged or were downregulated in MmuPV1 infected MPEK-BL6 cells. Conversely, RIG-I (DDX58), HERC6, IFI27, IRF7, OAS3, PLSCR1, STAT1 and IFI35 were significantly (>3-fold) upregulated at late time points p.i., 96, 120 and 144 hours, coincident with the suppression of early MmuPV1 mRNA. Conclusion Results obtained during my PhD project underlined a key role played by PV on the regulation of the early innate immune response. The low levels of TLRs activation may be related with the long time necessary for anal HPV clearance; however, TLR over-expression may be associated with pathological roles and may enhance the risk of HPV-related cancers. Moreover, we demonstrated that anal Hr HPV infection could inactivate IFN-mediated innate response due to lack of activation of ISGs. Interestingly, Hr HPV infection might inhibit the innate immune response by reducing NK cells activation, favouring the development of high-grade HPV-related lesions. Finally, our in vitro findings suggested that ISGs complex are triggered by MmuPV1 infection and act to downregulate MmuPV1 early mRNA in the tissue culture model.

Produzione scientifica

11573/1681572 - 2023 - In Vitro Virucidal Effects of Ultraviolet Light Prototypes on RNA viruses
Fracella, Matteo; Scordio, Mirko; Sorrentino, Leonardo; D'auria, Alessandra; Ingenito, Raffaele; Gentile, Massimo; Pierangeli, Alessandra; Antonelli, Guido; Scagnolari, Carolina; Frasca, Federica - 01a Articolo in rivista
rivista: NEW MICROBIOLOGICA (-Pavia : Edizioni Internazionali, 2004 precedente: -Bologna: Luigi Ponzio e figlio) pp. 161-169 - issn: 1121-7138 - wos: WOS:001007662400007 (0) - scopus: 2-s2.0-85160506571 (1)

11573/1655069 - 2022 - High prevalence of Merkel cell polyomavirus is associated with dysregulation in transcript levels of TLR9 and type I IFNs in a large cohort of CF patients from the Italian (Lazio) reference center for cystic fibrosis
Bitossi, Camilla; Viscido, Agnese; Prezioso, Carla; Brazzini, Gabriele; Trancassini, Maria; Borrazzo, Cristian; Passerini, Sara; Frasca, Federica; Scordio, Mirko; Sorrentino, Leonardo; Oliveto, Giuseppe; Fracella, Matteo; D'auria, Alessandra; Selvaggi, Carla; Cimino, Giuseppe; Midulla, Fabio; Pierangeli, Alessandra; Antonelli, Guido; Moens, Ugo; Pietropaolo, Valeria Antonietta; Scagnolari, Carolina - 01a Articolo in rivista
rivista: MICROBIAL PATHOGENESIS (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL: asianfo@elsevier.com, tcb@elsevier.co.UK, INTERNET: http://www.elsevier.com, http://www.elsevier.com/locate/shpsa/, Fax: 011 44 1865 843010) pp. 1-11 - issn: 0882-4010 - wos: WOS:000888223600001 (1) - scopus: 2-s2.0-85134182314 (1)

11573/1630792 - 2022 - Anti-IFN-α/-ω neutralizing antibodies from COVID-19 patients correlate with downregulation of IFN response and laboratory biomarkers of disease severity
Frasca, Federica; Scordio, Mirko; Santinelli, Letizia; Gabriele, Lucia; Gandini, Orietta; Criniti, Anna; Pierangeli, Alessandra; Angeloni, Antonio; Mastroianni, Claudio M.; D'ettorre, Gabriella; Viscidi, Raphael P.; Antonelli, Guido; Scagnolari, Carolina - 01a Articolo in rivista
rivista: EUROPEAN JOURNAL OF IMMUNOLOGY (Wiley-VCH Verlag GmBH:PO Box 101161, D 69451 Weinheim Germany:011 49 6201 606147, EMAIL: service@wiley-vch.de, INTERNET: http://www.wiley-vch.de, Fax: 011 49 6201 606328) pp. 1-9 - issn: 0014-2980 - wos: WOS:000794181400001 (24) - scopus: 2-s2.0-85128826578 (20)

11573/1652068 - 2022 - Chapter 15 MicroRNAs and the immune system
Frasca, Federica; Scordio, Mirko; Scagnolari, Carolina - 02a Capitolo o Articolo
libro: MicroRNA From Bench to Bedside - (9780323897747)

11573/1655133 - 2022 - The non-functional ACE2 isoform, but not the SARS-CoV-2 receptor, is induced as an interferon-stimulated gene, in SARS-CoV-2 infected adults
Oliveto, Giuseppe; Scagnolari, Carolina; Frasca, Federica; Sorrentino, Leonardo; Matera, Luigi; Nenna, Raffaella; Viscido, Agnese; Scordio, Mirko; Petrarca, Laura; Maria Zicari, Anna; Gentilini, Elio; D'ettorre, Gabriella; Ceccarelli, Giancarlo; Midulla, Fabio; Antonelli, Guido; Pierangeli, Alessandra - 01a Articolo in rivista
rivista: CYTOKINE (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL: asianfo@elsevier.com, tcb@elsevier.co.UK, INTERNET: http://www.elsevier.com, http://www.elsevier.com/locate/shpsa/, Fax: 011 44 1865 843010) pp. 1-5 - issn: 1043-4666 - wos: WOS:000879853200002 (0) - scopus: 2-s2.0-85135811587 (0)

11573/1617984 - 2022 - Analysis of serum microRNAs and rs2910164 GC single-nucleotide polymorphism of miRNA-146a in COVID-19 patients
Pinacchio, Claudia; Scordio, Mirko; Santinelli, Letizia; Frasca, Federica; Sorrentino, Leonardo; Bitossi, Camilla; Oliveto, Giuseppe; Viscido, Agnese; Ceci, Flavio Maria; Celani, Luigi; Ceccarelli, Giancarlo; Antonelli, Guido; Mastroianni, Claudio Maria; D'ettorre, Gabriella; Scagnolari, Carolina - 01a Articolo in rivista
rivista: JOURNAL OF IMMUNOASSAY & IMMUNOCHEMISTRY (Marcel Dekker Incorporated:270 Madison Avenue:New York, NY 10016:(800)228-1160, (212)696-9000, EMAIL: bookorders@dekker.com, INTERNET: http://www.dekker.com, Fax: (212)685-4540) pp. 347-364 - issn: 1532-1819 - wos: (0) - scopus: 2-s2.0-85126045598 (6)

11573/1649256 - 2022 - Potential Use of Tea Tree Oil as a Disinfectant Agent against Coronaviruses. A Combined Experimental and Simulation Study
Romeo, Alice; Iacovelli, Federico; Scagnolari, Carolina; Scordio, Mirko; Frasca, Federica; Condò, Roberta; Ammendola, Serena; Gaziano, Roberta; Anselmi, Maurizio; Divizia, Maurizio; Falconi, Mattia - 01a Articolo in rivista
rivista: MOLECULES (Basel: MDPI Berlin: Springer, 1996-) pp. 1-19 - issn: 1420-3049 - wos: WOS:000817504100001 (13) - scopus: 2-s2.0-85131671837 (13)

11573/1660796 - 2022 - High frequency of neutralizing antibodies to type I Interferon in HIV-1 patients hospitalized for COVID-19
Scordio, Mirko; Frasca, Federica; Santinelli, Letizia; Sorrentino, Leonardo; Pierangeli, Alessandra; Turriziani, Ombretta; Mastroianni, Claudio M; Antonelli, Guido; Viscidi, Raphael P; D'ettorre, Gabriella; Scagnolari, Carolina - 01f Lettera, Nota
rivista: CLINICAL IMMUNOLOGY (New York, NY: Elsevier Science Amsterdam: Elsevier Orlando FL: Academic Press, c1999-) pp. 109068- - issn: 1521-6616 - wos: WOS:000834539600004 (1) - scopus: 2-s2.0-85134721868 (1)

11573/1613623 - 2022 - Distribution of Interferon Lambda 4 Single Nucleotide Polymorphism rs11322783 Genotypes in Patients with COVID-19
Sorrentino, L.; Silvestri, V.; Oliveto, G.; Scordio, M.; Frasca, F.; Fracella, M.; Bitossi, C.; D'auria, A.; Santinelli, L.; Gabriele, L.; Pierangeli, A.; Mastroianni, C. M.; D'ettorre, G.; Antonelli, G.; Caruz, A.; Ottini, L.; Scagnolari, C. - 01a Articolo in rivista
rivista: MICROORGANISMS (Basel : MDPI) pp. 1-11 - issn: 2076-2607 - wos: WOS:000771612800001 (4) - scopus: 2-s2.0-85124013424 (4)

11573/1473193 - 2021 - SARS-CoV-2 Entry Genes Expression in Relation with Interferon Response in Cystic Fibrosis Patients
Bitossi, Camilla; Frasca, Federica; Viscido, Agnese; Oliveto, Giuseppe; Scordio, Mirko; Belloni, Laura; Cimino, Giuseppe; Pietropaolo, Valeria; Gentile, Massimo; D'ettorre, Gabriella; Midulla, Fabio; Trancassini, Maria; Antonelli, Guido; Pierangeli, Alessandra; Scagnolari, Carolina - 01a Articolo in rivista
rivista: MICROORGANISMS (Basel : MDPI) pp. 93- - issn: 2076-2607 - wos: WOS:000610585800001 (3) - scopus: 2-s2.0-85099252081 (4)

11573/1614125 - 2021 - Potential IFNγ modulation of inflammasome pathway in Chlamydia trachomatis infected synovial cells
Filardo, Simone; Di Pietro, Marisa; Frasca, Federica; Diaco, Fabiana; Scordio, Mirko; Antonelli, Guido; Scagnolari, Carolina; Sessa, Rosa - 01a Articolo in rivista
rivista: LIFE (Basel: MDPI) pp. 1-14 - issn: 2075-1729 - wos: WOS:000739007300001 (4) - scopus: 2-s2.0-85122373641 (4)

11573/1561018 - 2021 - KI and WU polyomavirus in respiratory samples of sars‐cov‐2 infected patients
Prezioso, C.; Moens, U.; Oliveto, G.; Brazzini, G.; Piacentini, F.; Frasca, F.; Viscido, A.; Scordio, M.; Guerrizio, G.; Rodio, D. M.; Pierangeli, A.; D'ettorre, G.; Turriziani, O.; Antonelli, G.; Scagnolari, C.; Pietropaolo, V. - 01a Articolo in rivista
rivista: MICROORGANISMS (Basel : MDPI) pp. 1-8 - issn: 2076-2607 - wos: WOS:000667401500001 (3) - scopus: 2-s2.0-85107421349 (4)

11573/1552054 - 2021 - Alteration of type I interferon response is associated with subclinical atherosclerosis in virologically suppressed HIV-1-infected male patients
Santinelli, L.; De Girolamo, G.; Borrazzo, C.; Vassalini, P.; Pinacchio, C.; Cavallari, E. N.; Statzu, M.; Frasca, F.; Scordio, M.; Bitossi, C.; Viscido, A.; Ceccarelli, G.; Mancone, M.; Mastroianni, C. M.; Antonelli, G.; D'ettorre, G.; Scagnolari, C. - 01a Articolo in rivista
rivista: JOURNAL OF MEDICAL VIROLOGY (-Hoboken, NJ : John Wiley & Sons Incorporated -[New York] Alan R. Liss, 1977-) pp. - - issn: 0146-6615 - wos: WOS:000646454600001 (4) - scopus: 2-s2.0-85105072127 (4)

11573/1481211 - 2021 - ACE2 expression is related to the interferon response in airway epithelial cells but is that functional for SARS-CoV-2 entry?
Scagnolari, Carolina; Bitossi, Camilla; Viscido, Agnese; Frasca, Federica; Oliveto, Giuseppe; Scordio, Mirko; Petrarca, Laura; Mancino, Enrica; Nenna, Raffaella; Riva, Elisabetta; De Vito, Corrado; Midulla, Fabio; Antonelli, Guido; Pierangeli, Alessandra - 01a Articolo in rivista
rivista: CYTOKINE (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL: asianfo@elsevier.com, tcb@elsevier.co.UK, INTERNET: http://www.elsevier.com, http://www.elsevier.com/locate/shpsa/, Fax: 011 44 1865 843010) pp. 1-4 - issn: 1043-4666 - wos: WOS:000618934800003 (9) - scopus: 2-s2.0-85099677908 (11)

11573/1474219 - 2021 - Differential induction of type I and III interferon genes in the upper respiratory tract of patients with coronavirus disease 2019 (COVID-19)
Scagnolari, Carolina; Pierangeli, Alessandra; Frasca, Federica; Bitossi, Camilla; Viscido, Agnese; Oliveto, Giuseppe; Scordio, Mirko; Mazzuti, Laura; Di Carlo, Daniele; Gentile, Massimo; Solimini, Angelo; Ceccarelli, Giancarlo; Pugliese, Francesco; Mastroianni, Claudio Maria; D'ettorre, Gabriella; Turriziani, Ombretta; Antonelli, Guido - 01a Articolo in rivista
rivista: VIRUS RESEARCH (Elsevier BV:PO Box 211, 1000 AE Amsterdam Netherlands:011 31 20 4853757, 011 31 20 4853642, 011 31 20 4853641, EMAIL: nlinfo-f@elsevier.nl, INTERNET: http://www.elsevier.nl, Fax: 011 31 20 4853598) pp. - - issn: 0168-1702 - wos: WOS:000632452300009 (17) - scopus: 2-s2.0-85099815666 (21)

11573/1434155 - 2020 - High abundance of genus Prevotella is associated with dysregulation of IFN-I and T cell response in HIV-1-infected patients
Pinacchio, C.; Scagnolari, C.; Iebba, V.; Santinelli, L.; Innocenti, G. P.; Frasca, F.; Bitossi, C.; Scordio, M.; Oliveto, G.; Ceccarelli, G.; Antonelli, G.; Mastroianni, C. M.; D'ettorre, G. - 01a Articolo in rivista
rivista: AIDS ([London]: Lippincott Williams and Wilkins.) pp. 1467-1473 - issn: 1473-5571 - wos: WOS:000561277800005 (12) - scopus: 2-s2.0-85088222818 (13)

11573/1422271 - 2020 - No detection of SARS-CoV-2 in cystic fibrosis patients at the Regional (Lazio) Reference Center for CF in Italy
Scagnolari, Carolina; Bitossi, Camilla; Frasca, Federica; Viscido, Agnese; Oliveto, Giuseppe; Scordio, Mirko; De Vito, Corrado; Trancassini, Maria; Midulla, Fabio; Cimino, Giuseppe; Pierangeli, Alessandra; Antonelli, Guido - 01a Articolo in rivista
rivista: JOURNAL OF CYSTIC FIBROSIS (Elsevier Science Limited:Oxford Fulfillment Center, PO Box 800, Kidlington Oxford OX5 1DX United Kingdom:011 44 1865 843000, 011 44 1865 843699, EMAIL: asianfo@elsevier.com, tcb@elsevier.co.UK, INTERNET: http://www.elsevier.com, http://www.elsevier.com/locate/shpsa/, Fax: 011 44 1865 843010) pp. - - issn: 1569-1993 - wos: (0) - scopus: 2-s2.0-85086937601 (7)

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