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

Guillon, A.; Brea-Diakite, D.; Cezard, A.; Wacquiez, A.; Baranek, T.; Bourgeais, J.; Picou, F.; Vasseur, V.; Meyer, L.; Chevalier, C.; Auvet, A.; Carballido, J.M.; Desbarats, L.N.; Dingli, F.; Turtoi, A.; Gouellec, A. le; Fauvelle, F.; Donchet, A.; Crepin, T.; Hiemstra, P.S.; Paget, C.; Loew, D.; Herault, O.; Naffakh, N.; Goffic, R. le; Si-Tahar, M.

doi: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,...Show moreInfluenza 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.Show less

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