Abstract
The establishment of effective antiviral responses within host cells is intricately related to their metabolic status, shedding light on immunometabolism. In this study, we investigated the hypothesis that cellular reliance on glutamine metabolism contributes to the development of a potent antiviral response. We evaluated the antiviral response in the presence or absence of L-glutamine in the culture medium, revealing a bivalent response hinging on cellular metabolism. While certain interferon-stimulated genes (ISGs) exhibited higher expression in an oxidative phosphorylation (OXPHOS)-dependent manner, others were surprisingly upregulated in a glycolytic-dependent manner. This metabolic dichotomy was influenced in part by variations in IFN-β expression. We initially demonstrated that the presence of L-glutamine induced an enhancement of OXPHOS in A549 cells. Furthermore, in cells either stimulated poly:IC or infected with Dengue Virus and Zika Virus, a marked increase in ISGs expression was observed in a dose-dependent manner with L-glutamine supplementation. Interestingly, our findings unveiled a metabolic dependency in the expression of specific ISGs. In particular, genes such as ISG54, ISG12 and ISG15 exhibited heightened expression in cells cultured with L-glutamine, corresponding to higher OXPHOS rates and IFN-β signaling. Conversely, the expression of viperin and 2’-5’-oligoadenylate synthetase 1 was inversely related to L-glutamine concentration, suggesting a glycolysis-dependent regulation, confirmed by inhibition experiments. This study highlights the intricate interplay between cellular metabolism, especially glutaminergic and glycolytic, and the establishment of the canonical antiviral response characterized by the expression of antiviral effectors, potentially paving the way for novel strategies to modulate antiviral responses through metabolic interventions.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This version of the manuscript has been revised to improve figures clarity and update data according to reviewers' suggestions upon submission. Figure 2 revised; Figure 3 revised; Figure 5 revised; Figure 6 revised; Supplemental files updated; Section 3.2. has been updated to add a part on results obtain Dengue and Zika viruses.
Data Availability Statement
All data needed to evaluate the conclusions in the paper are present in the article and/or the Supplementary Materials. Additional data related to this paper are available from the corresponding author upon reasonable request.
Abbreviations
- 2-DG
- 2-deoxyglucose
- A549Dual
- A549-DualTM, expressing NF-κB-SEAP and IRF-Luc reporters
- GAS
- Gamma interferon activation site
- IFN
- Interferon
- IFNAR
- IFNs ⍺/β receptor
- IRF
- Interferon Regulatory Factor
- ISG
- Interferon Stimulated Gene
- ISRE
- IFN-stimulated response element
- mROS
- Mitochondrial reactive oxygen species
- OXPHOS
- Oxidative phosphorylation
- PIC
- Poly(I:C) (HMW) / LyoVec™
