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

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.

[Metabokines reviewed: Essential mediators of anti-infectious immunity]. / Les métabokines, des médiateurs essentiels de l'immunité anti-infectieuse.

Metabolism and immunity have long been classified in distinct research fields; however, the concept of immunometabolism has recently highlighted their close relationship. Immune cells in an infectious context undergo a metabolic reprogramming that leads to the accumulation of metabolites. Some of these metabolites, called metabokines, play a crucial role in anti-infectious immunity by having immunoregulatory and antimicrobial defence properties. On the one hand, metabokines regulate the response of host immune cells by modulating intracellular signalling and/or inducing post-translational modifications of proteins. On the other hand, metabokines can directly or indirectly target pathogens by inhibiting microbial metabolic pathways, restoring the sensitivity of bacteria to antibiotics, and disrupting viral replication cycles. These discoveries on metabokine properties could pave the way for the development of innovative anti-infectious metabolic treatments.

TITLE: Les métabokines, des médiateurs essentiels de l'immunité anti-infectieuse. ABSTRACT: Longtemps cloisonnés dans des domaines de recherche distincts, métabolisme énergétique et immunité ont un lien étroit, récemment mis en exergue par le concept d'immunométabolisme. Dans un contexte infectieux, des reprogrammations métaboliques peuvent en effet survenir dans les cellules immunitaires et aboutir à l'accumulation de divers métabolites, dont certains, appelés métabokines, possèdent des propriétés inattendues d'immunorégulation et de défense antimicrobienne. Ils jouent un rôle crucial dans l'immunité anti-infectieuse, en régulant la réponse des cellules immunitaires de l'hôte, mais aussi en ciblant directement ou indirectement les microorganismes pathogènes.