PMID- 35071051
OWN - NLM
STAT- MEDLINE
DCOM- 20220128
LR  - 20220128
IS  - 2235-2988 (Electronic)
IS  - 2235-2988 (Linking)
VI  - 11
DP  - 2021
TI  - Influenza Virus Down-Modulates G6PD Expression and Activity to Induce Oxidative 
      Stress and Promote Its Replication.
PG  - 804976
LID - 10.3389/fcimb.2021.804976 [doi]
LID - 804976
AB  - Influenza virus infection induces oxidative stress in host cells by decreasing 
      the intracellular content of glutathione (GSH) and increasing reactive oxygen 
      species (ROS) level. Glucose-6-phosphate dehydrogenase (G6PD) is responsible for 
      the production of reducing equivalents of nicotinamide adenine dinucleotide 
      phosphate (NADPH) that is used to regenerate the reduced form of GSH, thus 
      restoring redox homeostasis. Cells deficient in G6PD display elevated levels of 
      ROS and an increased susceptibility to viral infection, although the consequences 
      of G6PD modulation during viral infection remain to be elucidated. In this study, 
      we demonstrated that influenza virus infection decreases G6PD expression and 
      activity, resulting in an increase in oxidative stress and virus replication. 
      Moreover, the down regulation of G6PD correlated with a decrease in the 
      expression of nuclear factor erythroid 2-related factor 2 (NRF2), a key 
      transcription factor that regulates the expression of the antioxidant response 
      gene network. Also down-regulated in influenza virus infected cells was sirtuin 2 
      (SIRT2), a NADPH-dependent deacetylase involved in the regulation of G6PD 
      activity. Acetylation of G6PD increased during influenza virus infection in a 
      manner that was strictly dependent on SIRT2 expression. Furthermore, the use of a 
      pharmacological activator of SIRT2 rescued GSH production and NRF2 expression, 
      leading to decreased influenza virus replication. Overall, these data identify a 
      novel strategy used by influenza virus to induce oxidative stress and to favor 
      its replication in host cells. These observations furthermore suggest that 
      manipulation of metabolic and oxidative stress pathways could define new 
      therapeutic strategies to interfere with influenza virus infection.
CI  - Copyright (c) 2022 De Angelis, Amatore, Checconi, Zevini, Fraternale, Magnani, 
      Hiscott, De Chiara, Palamara and Nencioni.
FAU - De Angelis, Marta
AU  - De Angelis M
AD  - Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 
      Department of Public Health and Infectious Diseases, Sapienza University of Rome, 
      Rome, Italy.
FAU - Amatore, Donatella
AU  - Amatore D
AD  - Scientific Department, Army Medical Center, Via di Santo Stefano Rotondo, Rome, 
      Italy.
FAU - Checconi, Paola
AU  - Checconi P
AD  - Department of Human Sciences and Promotion of the Quality of Life, San Raffaele 
      Roma Open University, IRCCS San Raffaele Roma, Rome, Italy.
FAU - Zevini, Alessandra
AU  - Zevini A
AD  - Pasteur Laboratory, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, 
      Italy.
FAU - Fraternale, Alessandra
AU  - Fraternale A
AD  - Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, 
      Italy.
FAU - Magnani, Mauro
AU  - Magnani M
AD  - Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, 
      Italy.
FAU - Hiscott, John
AU  - Hiscott J
AD  - Pasteur Laboratory, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, 
      Italy.
FAU - De Chiara, Giovanna
AU  - De Chiara G
AD  - Institute of Translational Pharmacology, National Research Council, Rome, Italy.
FAU - Palamara, Anna Teresa
AU  - Palamara AT
AD  - Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 
      Department of Public Health and Infectious Diseases, Sapienza University of Rome, 
      Rome, Italy.
AD  - Department of Infectious Diseases, Istituto Superiore di Sanita, Rome, Italy.
FAU - Nencioni, Lucia
AU  - Nencioni L
AD  - Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 
      Department of Public Health and Infectious Diseases, Sapienza University of Rome, 
      Rome, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220106
PL  - Switzerland
TA  - Front Cell Infect Microbiol
JT  - Frontiers in cellular and infection microbiology
JID - 101585359
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.1.1.49 (Glucosephosphate Dehydrogenase)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - *Glucosephosphate Dehydrogenase/genetics/metabolism
MH  - Glutathione/metabolism
MH  - *Orthomyxoviridae
MH  - Oxidative Stress
MH  - Reactive Oxygen Species
PMC - PMC8770543
OTO - NOTNLM
OT  - G6PD
OT  - NRF2
OT  - SIRT2
OT  - antioxidant response
OT  - glutathione
OT  - influenza virus
OT  - oxidative stress
OT  - redox state
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/01/25 06:00
MHDA- 2022/01/29 06:00
PMCR- 2021/01/01
CRDT- 2022/01/24 08:54
PHST- 2021/10/29 00:00 [received]
PHST- 2021/12/14 00:00 [accepted]
PHST- 2022/01/24 08:54 [entrez]
PHST- 2022/01/25 06:00 [pubmed]
PHST- 2022/01/29 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fcimb.2021.804976 [doi]
PST - epublish
SO  - Front Cell Infect Microbiol. 2022 Jan 6;11:804976. doi: 
      10.3389/fcimb.2021.804976. eCollection 2021.