FLAVIA TRIONFETTI

Dottoressa di ricerca

ciclo: XXXV


supervisore: Raffaele Strippoli
relatore: Raffaele Strippoli
co-supervisore: Raffaele Strippoli

Titolo della tesi: Mechanisms of response of Mesothelial Cells to viral infections: role of epigenetic HDAC1/2 regulation

The main focus of this doctoral thesis is the analysis of the response of mesothelial cells (MCs) to viral infections. As a cellular model we used first primary MCs from patients undergoing peritoneal dialysis (PD). In mammals, the recognition of pathogen infection occurs trough pathogen recognition receptors (PRRs), and among them, Toll-like receptor (TLR) family plays an important role. TLR3 is one of the TLRs associated to the recognition of viral infection and its role in MC plasticity has not been fully clarified yet. Here, we first analysed the TLRs pattern expression in primary MCs from dialyzed patients. We found that they express a specific subset composed by TRL1, TLR2, TLR3 and TLR5. We then, characterized the effects of TLR3 stimulation with Poly(I:C). We observed changes in MC cellular plasticity indicating the occurrence of bona fide mesothelial to mesenchymal transition (MMT), characterized by the acquisition of a spindle-like morphology, loss of epithelial markers and induction of mesenchymal markers, including the EMT master gene Snail. Moreover, Poly(I:C) stimulation promoted the induction of a pro-inflammatory response as shown by secretion of inflammatory cytokines and chemokines such as IL-1β, TNFα, IL-6, CXCL8 and CXCL10. Epigenetic reprogramming is a potentially relevant mechanism governing these changes in MC cell plasticity. Here, we analysed the impact of histone deacetylase (HDAC) inhibition using MS-275, an HDAC1/2 pharmacological inhibitor. Quantitative mass spectrometry analysis revealed several pathways altered by MS-275 treatment, including mesenchymal genes, actin cytoskeleton, extracellular matrix, and type-I interferon response regulation. Results obtained by proteomic analysis were then validated by Western blot analysis. Thus, we confirmed the role of MS-275 in promoting the expression of epithelial markers and in the downregulation of the IFNβ-driven response in Poly(I:C) stimulated MCs, which was linked to STAT1 tyrosine phosphorylation. To directly analyse the effects of viral infections on MCs, we then evaluated the response of a pleura mesothelial cell line, MeT5A cells, to SARS-CoV-2 infection. First, we found that MCs express the specific receptors/coreceptors ACE2, TMPRSS2, NRP1 and ADAM17. Moreover, MeT5A were found responsive to SARS-CoV-2 infection. MeT5A cells reacted to viral stimulation through a specific cytokine expression profile characterized by the predominance of an anti-inflammatory over a pro-inflammatory phenotype. Next, we evaluated the role of HDAC1/2 inhibition in SARS-CoV-2 infection. Treatment with MS-275 favoured SARS-CoV-2 infection and productive replication in MeT5A cells. We provided two different mechanisms by which HDAC1/2 inhibition can cause viral spreading in MCs. We found that MS-275 treatment both induced ACE2 and TMPPRSS2 expression and impaired interferon type-I response to SARS-CoV-2 infection. Mechanistically, treatment with MS-275 increased the H3 histone acetylation at ACE2 and TMPRSS2 promoter regions. Last, to find direct evidence of COVID-19 infection in mesothelium, we analysed 4 pleural autoptic samples of COVID-19 patients comparing them with 4 non COVID-19 -infected patients. Immunohistochemical analysis of samples from COVID-19 patients demonstrated a specific alteration of pleura characterized by disruption of the MC monolayer and invasion of the sub-mesothelial stroma by spindle-like MCs, but not evidence of direct MC infection by SARS-CoV-2. Overall, in this study we provided a characterization of changes in MC plasticity upon exposure to virus-related stimuli. Moreover, our data raise a concern on the use of class I HDACs pharmacological inhibitors such as MS-275 and derivatives in immunocompromised patients since they can potentiate SARS-CoV-2 infectivity.

Produzione scientifica

11573/1700487 - 2024 - HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling
Terri, Michela; Sandoval, Pilar; Bontempi, Giulio; Montaldo, Claudia; Tomero-Sanz, Henar; De Turris, Valeria; Trionfetti, Flavia; Pascual-Antón, Lucía; Clares-Pedrero, Irene; Battistelli, Cecilia; Valente, Sergio; Zwergel, Clemens; Mai, Antonello; Rosanò, Laura; Del Pozo, Miguel Ángel; Sánchez-Álvarez, Miguel; Cabañas, Carlos; Tripodi, Marco; López-Cabrera, Manuel; Strippoli, Raffaele - 01a Articolo in rivista
rivista: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (London : BioMed Central) pp. - - issn: 1756-9966 - wos: (0) - scopus: (0)

11573/1702828 - 2024 - Mechanisms of mesothelial cell response to viral infections: HDAC1-3 inhibition blocks poly(I:C)-induced type I interferon response and modulates the mesenchymal/inflammatory phenotype
Trionfetti, Flavia; Montaldo, Claudia; Caiello, Ivan; Bontempi, Giulio; Terri, Michela; Tiberi, Marta; Marchant, Vanessa; Domenici, Alessandro; Menè, Paolo; Cordani, Marco; Zwergel, Clemens; Prencipe, Giusi; Ruiz-Ortega, Marta; Valente, Sergio; Mai, Antonello; Tripodi, Marco; Strippoli, Raffaele - 01a Articolo in rivista
rivista: FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY (Lausanne : Frontiers Media SA, 2011-) pp. - - issn: 2235-2988 - wos: (0) - scopus: (0)

11573/1675051 - 2023 - Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective
López-Méndez, Tania B; Sánchez-Álvarez, Miguel; Trionfetti, Flavia; Pedraz, José L.; Tripodi, Marco; Cordani, Marco; Strippoli, Raffaele; González-Valdivieso, Juan - 01g Articolo di rassegna (Review)
rivista: CELL & BIOSCIENCE (London : BioMed Central) pp. - - issn: 2045-3701 - wos: WOS:000943663700001 (9) - scopus: 2-s2.0-85149920839 (6)

11573/1695097 - 2023 - BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress
Marchant, Vanessa; Trionfetti, Flavia; Tejedor-Santamaria, Lucia; Rayego-Mateos, Sandra; Rotili, Dante; Bontempi, Giulio; Domenici, Alessandro; Menè, Paolo; Mai, Antonello; Martín-Cleary, Catalina; Ortiz, Alberto; Ramos, Adrian M.; Strippoli, Raffaele; Ruiz-Ortega, Marta - 01a Articolo in rivista
rivista: ANTIOXIDANTS (Basel: MDPI) pp. 1-19 - issn: 2076-3921 - wos: (0) - scopus: 2-s2.0-85180466019 (0)

11573/1699768 - 2023 - BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress
Marchant, Vanessa; Trionfetti, Flavia; Tejedor-Santamaria, Lucia; Rayego-Mateos, Sandra; Rotili, Dante; Bontempi, Giulio; Domenici, Alessandro; Mene', Paolo; Mai, Antonello; Martín-Cleary, Catalina; Ortiz, Alberto; Ramos, Adrian M; Strippoli, Raffaele; Ruiz-Ortega, Marta - 01a Articolo in rivista
rivista: ANTIOXIDANTS (Basel: MDPI) pp. - - issn: 2076-3921 - wos: WOS:001137851500001 (0) - scopus: 2-s2.0-85180466019 (0)

11573/1696065 - 2023 - HDAC1-3 inhibition increases SARS-CoV-2 replication and productive infection in lung mesothelial and epithelial cells
Trionfetti, Flavia; Alonzi, Tonino; Bontempi, Giulio; Terri, Michela; Battistelli, Cecilia; Montaldo, Claudia; Repele, Federica; Rotili, Dante; Valente, Sergio; Zwergel, Clemens; Matusali, Giulia; Maggi, Fabrizio; Goletti, Delia; Tripodi, Marco; Mai, Antonello; Strippoli, Raffaele - 01a Articolo in rivista
rivista: FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY (Lausanne : Frontiers Media SA, 2011-) pp. - - issn: 2235-2988 - wos: (0) - scopus: (0)

11573/1675041 - 2023 - Novel Aspects of the Immune Response Involved in the Peritoneal Damage in Chronic Kidney Disease Patients under Dialysis
Trionfetti, Flavia; Marchant, Vanessa; González-Mateo, Guadalupe T.; Kawka, Edyta; Márquez-Expósito, Laura; Ortiz, Alberto; López-Cabrera, Manuel; Ruiz-Ortega, Marta; Strippoli, Raffaele - 01g Articolo di rassegna (Review)
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 5763- - issn: 1422-0067 - wos: WOS:000955473500001 (1) - scopus: 2-s2.0-85151113415 (1)

11573/1691462 - 2023 - POLY(I:C) INDUCES MORPHOLOGICAL CHANGES AND TYPE I INTERFERON-MEDIATED INFLAMMATORY RESPONSE IN MESOTHELIAL CELLS FROM PERITONEUM
Trionfetti, Flavia; Marchant, Vanessa; Terri, Michela; Bontempi, Giulio; Domenici, Alessandro; Mene, Paolo; Ruiz-Ortega, Marta; Strippoli, Raffaele - 01h Abstract in rivista
rivista: NEPHROLOGY DIALYSIS TRANSPLANTATION (Oxford: Oxford University Press.) pp. 1164-1164 - issn: 1460-2385 - wos: WOS:001022961100156 (0) - scopus: (0)

11573/1663108 - 2022 - Clinical Trials Involving Chemotherapy- Based Nanocarriers in Cancer Therapy: State of the Art and Future Directions
Lopez-Mendez, Tania B.; Strippoli, Raffaele; Trionfetti, Flavia; Calvo, Pilar; Cordani, Marco; Juan Gonzalez-Valdivieso, And - 02a Capitolo o Articolo
libro: Cancer Nanotechnology - ()

11573/1605129 - 2022 - SYNCRIP Modulates the Epithelial-Mesenchymal Transition in Hepatocytes and HCC Cells
Riccioni, V.; Trionfetti, F.; Montaldo, C.; Garbo, S.; Marocco, F.; Battistelli, C.; Marchetti, A.; Strippoli, R.; Amicone, L.; Cicchini, C.; Tripodi, M. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. 913- - issn: 1661-6596 - wos: WOS:000748109700001 (5) - scopus: 2-s2.0-85122801338 (5)

11573/1627263 - 2022 - SYNCRIP modulates the epithelial-mesenchymal transition in hepatocytes and HCC Cells
Riccioni, V.; Trionfetti, F.; Montaldo, C.; Garbo, S.; Marocco, F.; Battistelli, C.; Marchetti, A.; Strippoli, R.; Amicone, L.; Cicchini, C.; Tripodi, M. - 04f Poster
congresso: ABCD National Ph.D. Meeting (Salerno; Italy)
libro: National Ph.D. Meeting Abstracts book - ()

11573/1612876 - 2022 - Exposure to b‐LED light while exerting antimicrobial activity on Gram‐negative and ‐positive bacteria promotes transient EMT‐like changes and growth arrest in keratinocytes
Terri, M.; Mancianti, N.; Trionfetti, F.; Casciaro, B.; De Turris, V.; Raponi, G.; Bontempi, G.; Montaldo, C.; Domenici, A.; Mene', P.; Mangoni, M. L.; Strippoli, R. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:000755651500001 (1) - scopus: 2-s2.0-85124280849 (2)

11573/1586405 - 2021 - Autophagy and the lysosomal system in cancer
Kumar, Suresh; Sánchez-Álvarez, Miguel; Lolo, Fidel-Nicolás; Trionfetti, Flavia; Strippoli, Raffaele; Marco, Cordani - 01g Articolo di rassegna (Review)
rivista: CELLS (Basel: mdpi-Molecular Diversity Preservation International) pp. - - issn: 2073-4409 - wos: WOS:000715401800001 (18) - scopus: 2-s2.0-85116992319 (22)

11573/1610922 - 2021 - Pleural mesothelial cells modulate the inflammatory/profibrotic response during SARS-CoV-2 infection
Matusali, Giulia; Trionfetti, Flavia; Bordoni, Veronica; Nardacci, Roberta; Falasca, Laura; Colombo, Daniele; Terri, Michela; Montaldo, Claudia; Castilletti, Concetta; Mariotti, Davide; Del Nonno, Franca; Capobianchi, Maria Rosaria; Agrati, Chiara; Tripodi, Marco; Strippoli, Raffaele - 01a Articolo in rivista
rivista: FRONTIERS IN MOLECULAR BIOSCIENCES (Lausanne : Frontiers Media S.A., 2014-) pp. - - issn: 2296-889X - wos: WOS:000893554700001 (3) - scopus: 2-s2.0-85121011510 (6)

11573/1571274 - 2021 - Fibrogenic signals persist in DAA-treated HCV patients after sustained virological response
Montaldo, Claudia; Terri, Michela; Riccioni, Veronica; Battistelli, Cecilia; Bordoni, Veronica; D'offizi, Gianpiero; Prado, Maria Giulia; Trionfetti, Flavia; Vescovo, Tiziana; Tartaglia, Eleonora; Strippoli, Raffaele; Agrati, Chiara; Tripodi, Marco - 01a Articolo in rivista
rivista: JOURNAL OF HEPATOLOGY (Blackwell Munksgaard:PO Box 2148, Periodicals Department, DK-1016 Copenhagen K Denmark:011 45 33 755913, EMAIL: agentservices@oxon.blackwellpublishing.com, INTERNET: http://www.blackwellmunksgaard.com, Fax: 011 45 77 333377) pp. 1301-1311 - issn: 0168-8278 - wos: WOS:000727375100007 (13) - scopus: 2-s2.0-85114987180 (16)

11573/1550677 - 2021 - Mechanisms of peritoneal fibrosis: focus on immune cells-peritoneal stroma interactions
Terri, Michela; Trionfetti, Flavia; Montaldo, Claudia; Cordani, Marco; Tripodi, Marco; Lopez-Cabrera, Manuel; Strippoli, Raffaele - 01g Articolo di rassegna (Review)
rivista: FRONTIERS IN IMMUNOLOGY (Lausanne : Frontiers Research Foundation, 2010-) pp. - - issn: 1664-3224 - wos: WOS:000639137900001 (38) - scopus: 2-s2.0-85104013369 (41)

11573/1441893 - 2020 - Y haplogroup diversity of the Dominican Republic. Reconstructing the effect of the European colonization and the trans-Atlantic slave trades
D'atanasio, Eugenia; Trionfetti, Flavia; Bonito, Maria; Sellitto, Daniele; Coppa, Alfredo; Berti, Andrea; Trombetta, Beniamino; Cruciani, Fulvio - 01a Articolo in rivista
rivista: GENOME BIOLOGY AND EVOLUTION (Oxford : Oxford University Press) pp. 1579-1590 - issn: 1759-6653 - wos: WOS:000599652200008 (4) - scopus: 2-s2.0-85092332074 (4)

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