Metabolic Dependency Shapes Bivalent Antiviral Response in Host Cells in Response to Poly:IC: The Role of Glutamine

Author:

Lebeau Grégorie12ORCID,Paulo-Ramos Aurélie2,Hoareau Mathilde2,El Safadi Daed1,Meilhac Olivier2ORCID,Krejbich-Trotot Pascale1ORCID,Roche Marjolaine1,Viranaicken Wildriss12ORCID

Affiliation:

1. PIMIT—Processus Infectieux en Milieu Insulaire Tropical, INSERM UMR 1187, CNRS 9192, IRD 249, Plateforme CYROI, Université de La Réunion, 97490 Sainte-Clotilde, France

2. Diabète Athérothrombose Réunion Océan Indien (DéTROI), INSERM UMR 1188, Campus Santé de Terre Sainte, Université de La Réunion, 97410 Saint-Pierre, France

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 interferon-β (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 by 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.

Funder

Conseil Régional de La Réunion

Publisher

MDPI AG

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