MARTA DE ANGELIS

Dottoressa di ricerca

ciclo: XXXIII


supervisore: Prof. Lucia Nencioni
co-supervisore: Prof. Lucia Nencioni

Titolo della tesi: Influenza virus induces oxidative stress by modulating G6PD enzyme to promote its replication

Respiratory viruses use different strategies to manipulate host cell machinery to their advantage, including the modulation of redox state. Among respiratory viruses, influenza virus replication is favored by pro-oxidant conditions mainly determined by an increase of Reactive Oxygen Species (ROS) production and decrease of intracellular glutathione (GSH) content. Glucose-6-phosphate dehydrogenase (G6PD) activity is responsible for the production of reducing equivalents of nicotinamide adenine dinucleotide phosphate (NADPH), used for regenerating GSH. It has been reported that G6PD-deficiency condition increases the susceptibility to viral infections but the modulation of G6PD enzyme during the infection and the mechanisms by which the viruses induce oxidative stress through this pathway are not well elucidated. G6PD enzyme is regulated at different levels into cell. Nrf2 transcription factor is activated under a stressful condition and transcribes antioxidant genes including G6PD, playing a central role in the antioxidant response. At the same time G6PD is also regulated at the activity level by the deacetylase SIRT2, a NADPH-dependent deacetylase, through the deacetylation of lysine regulatory site of the enzyme. In this study I evaluated the modulation of G6PD expression and activity during influenza virus infection. I analysed the role of G6PD down-regulation during influenza virus replication and its correlation with oxidative stress induction. Afterwards, I verified the mechanisms by which influenza virus modulates the enzyme and the possible effects of reducing compounds on virus replication. With the beginning of COVID19 outbreak my studies were focused on SARS-CoV-2 pathogenesis. Therefore, I analysed whether the new coronavirus modulates the same cell pathways for its replication comparing to influenza virus infection. Finally, I evaluated the possibility to use antioxidant compounds able to modulate specific redox-related pathways, against respiratory viruses. The results showed that G6PD expression and activity were reduced after the infection and their down-regulation correlated with the reduction of Nrf2 and SIRT2 expression, respectively. The acetylation of G6PD increased during influenza virus infection and its activity was strictly dependent on SIRT2 expression. The use of SIRT2 activator induced a rescue of reducing conditions in terms of GSH production, Nrf2 and G6PD expression that correlated with a decrease of viral replication. SARS-CoV-2 infection determined the same modulation of the antioxidant response compared to influenza virus. The use of specific antioxidant molecules was able to impair the replication of influenza virus by recovering the intracellular redox balance in terms of increased expression of Nrf2 and G6PD, or by modulating ACE2, that is involved in the SARS-CoV-2 infection and in regulating the intracellular redox state. Overall these data identify a new cellular pathway used by influenza virus to induce oxidative stress and to favor its replication in host cells. Furthermore, the use of molecules able to restore reducing conditions into cell and able to manipulate specific redox-related pathways may open to new cell-targeting strategies against respiratory viruses infection.

Produzione scientifica

  • 11573/1601812 - 2021 - JQ1, inibitore delle proteine BET, riduce i fattori di virulenza e la patogenicità di Aspergillus fumigatus. (04d Abstract in atti di convegno)
    OREKHOVA, ANASTASIA; DE ANGELIS, MARTA; PROTTO, VIRGINIA; ROTILI, DANTE; MAI, ANTONELLO; SIMONETTI, GIOVANNA
  • 11573/1662482 - 2022 - Multicomponent synthesis of diaminopurine and guanine PNA’s analogues active against influenza a virus from prebiotic compounds (01a Articolo in rivista)
    DE ANGELIS, MARTA; FIORAVANTI, RAOUL; NENCIONI, LUCIA
  • 11573/1690682 - 2023 - Dysregulation of intracellular redox homeostasis by the SARS-CoV-2 ORF6 protein (01a Articolo in rivista)
    DE ANGELIS, MARTA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1135927 - 2018 - Differential redox state contributes to sex disparities in the response to influenza virus infection in male and female mice (01a Articolo in rivista)
    CELESTINO, IGNACIO; AMATORE, DONATELLA; DE ANGELIS, MARTA; COLUCCIO, PAOLO; ALUNNI FEGATELLI, DANILO; MANCINELLI, ROMINA; MAMMOLA, CATERINA LOREDANA; VESTRI, ANNA RITA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1135921 - 2018 - Antiviral and antioxidant activity of a hydroalcoholic extract from Humulus lupulus L. (01a Articolo in rivista)
    DI SOTTO, ANTONELLA; CHECCONI, PAOLA; CELESTINO, IGNACIO; CARISSIMI, STEFANIA; DE ANGELIS, MARTA; ROSSI, VALERIA; TONIOLO, CHIARA; MARTINOLI, LUCIA; DI GIACOMO, SILVIA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1691722 - 2022 - Valorisation of an Italian mountain variety of Echinacea purpurea (L.) Moench: a sustainable strategy for medicinal plant production (04d Abstract in atti di convegno)
    PERCACCIO, ESTER; DE ANGELIS, MARTA; NENCIONI, LUCIA; DI GIACOMO, SILVIA; DI SOTTO, ANTONELLA
  • 11573/1684486 - 2023 - Identification of anti-influenza A compounds inhibiting the NS-1 viral protein using a type I IFN-driven screening strategy (01a Articolo in rivista)
    DE ANGELIS, MARTA; NENCIONI, LUCIA
  • 11573/1013437 - 2017 - Antitumor effects of epidrug/IFN alpha combination driven by modulated gene signatures in both colorectal cancer and dendritic cells (01a Articolo in rivista)
    LICURSI, VALERIO; BUONCERVELLO, MARIA; DEL VECCHIO, GIORGIA; DE ANGELIS, MARTA; NEGRI, RODOLFO; PRESUTTI, CARLO
  • 11573/1680087 - 2023 - NRF2 antioxidant response and interferon-stimulated genes are differentially expressed in respiratory-syncytial-virus- and rhinovirus-infected hospitalized children (01a Articolo in rivista)
    SORRENTINO, LEONARDO; TOSCANELLI, WALTER; FRACELLA, MATTEO; DE ANGELIS, MARTA; FRASCA, FEDERICA; SCAGNOLARI, CAROLINA; PETRARCA, LAURA; NENNA, RAFFAELLA; MIDULLA, FABIO; PALAMARA, ANNA TERESA; NENCIONI, LUCIA; PIERANGELI, ALESSANDRA
  • 11573/1242259 - 2019 - Counteraction of HCV-induced oxidative stress concurs to establish chronic infection in liver cell cultures (01a Articolo in rivista)
    AMATORE, DONATELLA; DE ANGELIS, MARTA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1690684 - 2023 - Echopvir. A mixture of echinacea and hop extracts endowed with cytoprotective, immunomodulatory and antiviral properties (01a Articolo in rivista)
    PERCACCIO, ESTER; DE ANGELIS, MARTA; MAZZANTI, GABRIELA; DI GIACOMO, SILVIA; NENCIONI, LUCIA; DI SOTTO, ANTONELLA
  • 11573/1335944 - 2019 - Synthesis of stilbene and chalcone inhibitors of influenza A virus by SBA-15 Supported Hoveyda-Grubbs metathesis (01a Articolo in rivista)
    DE ANGELIS, MARTA; DOLFA, CAMILLA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1662647 - 2022 - In-silico functional metabolic pathways associated to Chlamydia trachomatis genital infection (01a Articolo in rivista)
    FILARDO, SIMONE; DI PIETRO, MARISA; DE ANGELIS, MARTA; BRANDOLINO, GABRIELLA; PORPORA, MARIA GRAZIA; SESSA, ROSA
  • 11573/1568303 - 2021 - Aminomalononitrile inspired prebiotic chemistry as a novel multicomponent tool for the synthesis of imidazole and purine derivatives with anti-influenza A virus activity (01a Articolo in rivista)
    DE ANGELIS, MARTA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1487295 - 2021 - Laccase-catalyzed 1,4-dioxane-mediated synthesis of belladine N-oxides with anti-influenza A virus activity (01a Articolo in rivista)
    NENCIONI, LUCIA; DE ANGELIS, MARTA; PROTTO, VIRGINIA
  • 11573/1487277 - 2021 - Temporin G, an amphibian antimicrobial peptide against influenza and parainfluenza respiratory viruses. Insights into biological activity and mechanism of action (01a Articolo in rivista)
    DE ANGELIS, MARTA; CASCIARO, BRUNO; MARCOCCI, MARIA ELENA; PALAMARA, ANNA TERESA; MANGONI, MARIA LUISA; NENCIONI, LUCIA
  • 11573/1530178 - 2021 - Intracellular redox-modulated pathways as targets for effective approaches in the treatment of viral infection (01g Articolo di rassegna (Review))
    DE ANGELIS, MARTA; NENCIONI, LUCIA; PALAMARA, ANNA TERESA
  • 11573/1540215 - 2021 - Investigation of Commiphora myrrha (Nees) Engl. oil and its main components for antiviral activity (01a Articolo in rivista)
    MADIA, VALENTINA NOEMI; DE ANGELIS, MARTA; DE VITA, DANIELA; MESSORE, ANTONELLA; DE LEO, ALESSANDRO; IALONGO, DAVIDE; TUDINO, VALERIA; GARZOLI, STEFANIA; SCIPIONE, LUIGI; PALAMARA, ANNA TERESA; DI SANTO, ROBERTO; NENCIONI, LUCIA; COSTI, ROBERTA
  • 11573/1568315 - 2021 - System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2. (01a Articolo in rivista)
    DE ANGELIS, MARTA; NENCIONI, LUCIA
  • 11573/1573420 - 2021 - STUDIO DELLE PROPRIETÀ CITOPROTETTIVE, ANTIVIRALI E IMMUNOMODULANTI DI UNA MISCELA DI ESTRATTI DI LUPPOLO (HUMULUS LUPULUS L.) ED ECHINACEA (ECHINACEA PURPUREA (L.) MOENCH) (14s Intervento a convegno non pubblicato)
    PERCACCIO, ESTER; DE ANGELIS, MARTA; NENCIONI, LUCIA; DI SOTTO, ANTONELLA
  • 11573/1585387 - 2021 - Rapid inactivation of SARS-CoV-2 with LED irradiation of visible spectrum wavelengths (01a Articolo in rivista)
    DE ANGELIS, MARTA; NENCIONI, LUCIA; PALAMARA, ANNA TERESA
  • 11573/1585389 - 2021 - Anti-influenza A virus activity and structure–activity relationship of a series of nitrobenzoxadiazole derivatives (01a Articolo in rivista)
    FIORENTINO, FRANCESCO; DE ANGELIS, MARTA; MENNA, MARTINA; ROVERE, ANNARITA; D'ACUNZO, FRANCESCA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA; ROTILI, DANTE; MAI, ANTONELLO
  • 11573/1612014 - 2022 - Influenza virus down-modulates G6PD expression and activity to induce oxidative stress and promote its replication (01a Articolo in rivista)
    DE ANGELIS, MARTA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1662483 - 2022 - Nitrostilbenes. Synthesis and biological evaluation as potential anti-influenza virus agents (01a Articolo in rivista)
    DE ANGELIS, MARTA; MITEVA, MARIYA TIMOTEY; DE CHIARA, GIOVANNA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1648551 - 2022 - Antifungal activity of the frog skin peptide Temporin G and its effect on Candida albicans virulence factors (01a Articolo in rivista)
    D'AURIA, FELICIA DIODATA; CASCIARO, BRUNO; DE ANGELIS, MARTA; MARCOCCI, MARIA ELENA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA; MANGONI, MARIA LUISA
  • 11573/1668164 - 2023 - Influenza virus replication is affected by glutaredoxin1-mediated protein deglutathionylation (01a Articolo in rivista)
    DE ANGELIS, MARTA; NENCIONI, LUCIA; PALAMARA, ANNA TERESA
  • 11573/1664310 - 2022 - Modulation of virulence-associated traits in Aspergillus fumigatus by BET Inhibitor JQ1 (01a Articolo in rivista)
    OREKHOVA, ANASTASIA; DE ANGELIS, MARTA; CACCIOTTI, ANDREA; REVERBERI, MASSIMO; ROTILI, DANTE; GIORGI, ALESSANDRA; PROTTO, VIRGINIA; BONINCONTRO, GRAZIANA; FIORENTINO, FRANCESCO; MAI, ANTONELLO; PALAMARA, ANNA TERESA; SIMONETTI, GIOVANNA
  • 11573/1648549 - 2022 - Ultrastructural damages to H1N1 influenza virus caused by vapor essential oils (01a Articolo in rivista)
    MADIA, VALENTINA NOEMI; TOSCANELLI, WALTER; DE VITA, DANIELA; DE ANGELIS, MARTA; MESSORE, ANTONELLA; IALONGO, DAVIDE; SCIPIONE, LUIGI; TUDINO, VALERIA; D'AURIA, FELICIA DIODATA; DI SANTO, ROBERTO; GARZOLI, STEFANIA; NENCIONI, LUCIA; COSTI, ROBERTA
  • 11573/1668166 - 2023 - Targeting SARS-CoV-2 by synthetic dual-acting thiol compounds that inhibit Spike/ACE2 interaction and viral protein production (01a Articolo in rivista)
    DE ANGELIS, MARTA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1414917 - 2020 - Redox-Modulating Agents in the Treatment of Viral Infections (01a Articolo in rivista)
    DE ANGELIS, MARTA; MARCOCCI, MARIA ELENA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1586609 - 2021 - Protective Role of Combined Polyphenols and Micronutrients against Influenza A Virus and SARS-CoV-2 Infection in vitro. (01a Articolo in rivista)
    DE ANGELIS, MARTA; AMBROSIO, LUIGINA; PALAMARA, ANNA TERESA; NENCIONI, LUCIA
  • 11573/1650902 - 2022 - The inhibition of DNA viruses by the amphibian antimicrobial peptide temporin G. A virological study addressing HSV-1 and JPCyV (01a Articolo in rivista)
    MARCOCCI, MARIA ELENA; PREZIOSO, CARLA; PROTTO, VIRGINIA; DE ANGELIS, MARTA; CASCIARO, BRUNO; MANGONI, MARIA LUISA; PALAMARA, ANNA TERESA; PIETROPAOLO, VALERIA ANTONIETTA; DE CHIARA, GIOVANNA; NENCIONI, LUCIA

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