Identification and characterization of GLDC as host susceptibility gene to severe influenza.
Animals
Disease Models, Animal
Enzyme Inhibitors
/ administration & dosage
Genetic Predisposition to Disease
Glycine Dehydrogenase (Decarboxylating)
/ genetics
Humans
Immunity, Innate
Influenza A Virus, H1N1 Subtype
/ growth & development
Influenza A Virus, H7N9 Subtype
/ growth & development
Influenza, Human
/ genetics
Mice, Inbred BALB C
Orthomyxoviridae Infections
/ drug therapy
Tacrolimus
/ administration & dosage
Treatment Outcome
Virus Replication
GLDC
antiviral response
genetic susceptibility
severe influenza
viral replication
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
pubmed:
1
12
2018
medline:
7
8
2019
entrez:
1
12
2018
Statut:
ppublish
Résumé
Glycine decarboxylase (GLDC) was prioritized as a candidate susceptibility gene to severe influenza in humans. The higher expression of GLDC derived from genetic variations may confer a higher risk to H7N9 and severe H1N1 infection. We sought to characterize GLDC as functional susceptibility gene that GLDC may intrinsically regulate antiviral response, thereby impacting viral replication and disease outcome. We demonstrated that GLDC inhibitor AOAA and siRNA depletion boosted IFNβ- and IFN-stimulated genes (ISGs) in combination with PolyI:C stimulation. GLDC inhibition and depletion significantly amplified antiviral response of type I IFNs and ISGs upon viral infection and suppressed the replication of H1N1 and H7N9 viruses. Consistently, GLDC overexpression significantly promoted viral replication due to the attenuated antiviral responses. Moreover, GLDC inhibition in H1N1-infected BALB/c mice recapitulated the amplified antiviral response and suppressed viral growth. AOAA provided potent protection to the infected mice from lethal infection, comparable to a standard antiviral against influenza viruses. Collectively, GLDC regulates cellular antiviral response and orchestrates viral growth. GLDC is a functional susceptibility gene to severe influenza in humans.
Identifiants
pubmed: 30498026
pii: emmm.201809528
doi: 10.15252/emmm.201809528
pmc: PMC6328914
pii:
doi:
Substances chimiques
32-ascomycinyloxyacetic acid
0
Enzyme Inhibitors
0
Glycine Dehydrogenase (Decarboxylating)
EC 1.4.4.2
Tacrolimus
WM0HAQ4WNM
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Informations de copyright
© 2018 The Authors. Published under the terms of the CC BY 4.0 license.
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