Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein
Antoine Guillon, Déborah Brea-Diakite, Adeline Cezard, Alan Wacquiez, Thomas Baranek, Jérôme Bourgeais, Frédéric Picou, Virginie Vasseur, Léa Meyer, Christophe Chevalier, Adrien Auvet, José M. Carballido, Lydie Nadal‐Desbarats, Florent Dingli, Andrei Turtoï, Audrey Le Gouëllec, Florence Fauvelle, Amélie Donchet, Thibaut Crépin, Pieter S. Hiemstra, Christophe Paget, Damarys Loew, Olivier Hérault, Nadia Naffakh, Ronan Le Goffic, Mustapha Si‐Tahar
Abstract
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. 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. The energy‐production metabolite succinate protects from pulmonary viral infection via post‐translational modification‐dependent interruption of the influenza replication cycle.