In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 7 ( 2023-7-13), p. e1010986-
Abstract:
Influenza A virus (IAV), like any other virus, provokes considerable modifications of its host cell’s metabolism. This includes a substantial increase in the uptake as well as the metabolization of glucose. Although it is known for quite some time that suppression of glucose metabolism restricts virus replication, the exact molecular impact on the viral life cycle remained enigmatic so far. Using 2-deoxy- d -glucose (2-DG) we examined how well inhibition of glycolysis is tolerated by host cells and which step of the IAV life cycle is affected. We observed that effects induced by 2-DG are reversible and that cells can cope with relatively high concentrations of the inhibitor by compensating the loss of glycolytic activity by upregulating other metabolic pathways. Moreover, mass spectrometry data provided information on various metabolic modifications induced by either the virus or agents interfering with glycolysis. In the presence of 2-DG viral titers were significantly reduced in a dose-dependent manner. The supplementation of direct or indirect glycolysis metabolites led to a partial or almost complete reversion of the inhibitory effect of 2-DG on viral growth and demonstrated that indeed the inhibition of glycolysis and not of N -linked glycosylation was responsible for the observed phenotype. Importantly, we could show via conventional and strand-specific qPCR that the treatment with 2-DG led to a prolonged phase of viral mRNA synthesis while the accumulation of genomic vRNA was strongly reduced. At the same time, minigenome assays showed no signs of a general reduction of replicative capacity of the viral polymerase. Therefore, our data suggest that the significant reduction in IAV replication by glycolytic interference occurs mainly due to an impairment of the dynamic regulation of the viral polymerase which conveys the transition of the enzyme’s function from transcription to replication.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010986
DOI:
10.1371/journal.ppat.1010986.g001
DOI:
10.1371/journal.ppat.1010986.g002
DOI:
10.1371/journal.ppat.1010986.g003
DOI:
10.1371/journal.ppat.1010986.g004
DOI:
10.1371/journal.ppat.1010986.g005
DOI:
10.1371/journal.ppat.1010986.g006
DOI:
10.1371/journal.ppat.1010986.g007
DOI:
10.1371/journal.ppat.1010986.t001
DOI:
10.1371/journal.ppat.1010986.s001
DOI:
10.1371/journal.ppat.1010986.s002
DOI:
10.1371/journal.ppat.1010986.s003
DOI:
10.1371/journal.ppat.1010986.s004
DOI:
10.1371/journal.ppat.1010986.s005
DOI:
10.1371/journal.ppat.1010986.s006
DOI:
10.1371/journal.ppat.1010986.s007
DOI:
10.1371/journal.ppat.1010986.s008
DOI:
10.1371/journal.ppat.1010986.s009
DOI:
10.1371/journal.ppat.1010986.s010
DOI:
10.1371/journal.ppat.1010986.s011
DOI:
10.1371/journal.ppat.1010986.s012
DOI:
10.1371/journal.ppat.1010986.s013
DOI:
10.1371/journal.ppat.1010986.s014
DOI:
10.1371/journal.ppat.1010986.s015
DOI:
10.1371/journal.ppat.1010986.s016
DOI:
10.1371/journal.ppat.1010986.s017
DOI:
10.1371/journal.ppat.1010986.s018
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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