@article {Cezard119, author = {Adeline Cezard and Antoine Guillon and Deborah Br{\'e}a-Diakite and Alan Wacquiez and Thomas Baranek and J{\'e}r{\^o}me Bourgeais and Fr{\'e}d{\'e}ric Picou and Virginie Vasseur and L{\'e}a Meyer and Adrien Auvet and Jos{\'e} M Carballido and Lydie Nadal Desbarats and Florent Dingli and Andrei Turtoi and Audrey Le Gouellec and Florence Fauvelle and Am{\'e}lie Donchet and Thibaut Cr{\'e}pin and Pieter S. Hiemstra and Christophe Paget and Damarys Loew and Olivier H{\'e}rault and Nadia Naffakh and Ronan Le Goffic and Mustapha Si-Tahar}, title = {The metabolite succinate inhibits influenza virus replication through succinylation and nuclear retention of the viral nucleoprotein}, volume = {8}, number = {suppl 8}, elocation-id = {119}, year = {2022}, doi = {10.1183/23120541.LSC-2022.119}, publisher = {European Respiratory Society}, abstract = {Influenza~causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during influenza infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we demonstrated that influenza virus infection induces a major reprogramming of lung metabolism. We focused on mitochondria-derived succinate that we found to accumulate both in the respiratory fluids of virus-challenged mice and of patients with influenza-related pneumonia. We found that 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 through the intranasal route showed reduced viral loads in lung tissues and had an increased survival rate compared to control animals. The antiviral mechanism involves a succinate-dependent post-translational modification, i.e. succinylation, of the viral nucleoprotein (NP). Succinylation of NP could alter its electrostatic interactions with viral RNA and could further impair the formation and trafficking of viral ribonucleoprotein complexes. Hence, succinate efficiently disrupts the influenza replication cycle; this opens up new avenues for improved treatment of influenza pneumonia.FootnotesCite this article as ERJ Open Research 2022; 8: Suppl. 8, 119.This article was presented at the 2022 ERS Lung Science Conference, in session {\textquotedblleft}Poster Session 2{\textquotedblright}.This is an ERS Lung Science Conference abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).}, URL = {https://openres.ersjournals.com/content/8/suppl_8/119}, eprint = {https://openres.ersjournals.com/content}, journal = {ERJ Open Research} }