Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein

• Published in: The EMBO journal Vol. 41; no. 12; pp. e108306 - n/a
• Main Authors: Guillon, Antoine, Brea‐Diakite, Deborah, Cezard, Adeline, Wacquiez, Alan, Baranek, Thomas, Bourgeais, Jérôme, Picou, Frédéric, Vasseur, Virginie, Meyer, Léa, Chevalier, Christophe, Auvet, Adrien, Carballido, José M, Nadal Desbarats, Lydie, Dingli, Florent, Turtoi, Andrei, Le Gouellec, Audrey, Fauvelle, Florence, Donchet, Amélie, Crépin, Thibaut, Hiemstra, Pieter S, Paget, Christophe, Loew, Damarys, Herault, Olivier, Naffakh, Nadia, Le Goffic, Ronan, Si‐Tahar, Mustapha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-06-2022; Blackwell Publishing Ltd; EMBO Press; John Wiley and Sons Inc
• Subjects: antiviral; Antiviral activity; Bronchus; Electrostatic properties; EMBO19; EMBO21; EMBO23; Epithelial cells; Epithelium; Human health and pathology; Infections; Inflammation; Influenza; Influenza A; Lavage; Life Sciences; Lungs; metabokine; Metabolism; Metabolites; Metabolomics; Mitochondria; Morbidity; Multiplication; Patients; Perturbation; Pneumonia; Retention; signaling; virus; Viruses; influenza; signaling; metabokine; virus; antiviral
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2021108306

Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria‐derived succinate that accumulated both in the respiratory fluids of virus‐challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity
in vitro
as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus‐triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate‐dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia.
Synopsis
Metabolic defense mechanisms of lung epithelial cells exposed to influenza virus infection remain poorly understood. Here, combined metabolomics,
in vitro
and
in vivo
infection assays reveal a surprising anti‐viral role of energy production metabolite succinate in the airways, suggesting new avenues for improved treatment of influenza pneumonia.
Influenza A virus (IAV) infection of mice increases succinate levels in the airways.
IAV‐infected patients show elevated succinate levels in tracheal aspirates.
Succinate inhibits IAV infection through succinylation and nuclear retention of the viral nucleoprotein.
Succinate restores metabolic dysregulation in IAV‐infected lung epithelial cells and impairs acute influenza pneumonia
in vivo
.
Graphical Abstract
The energy‐production metabolite succinate protects from pulmonary viral infection via post‐translational modification‐dependent interruption of the influenza replication cycle.