Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may... 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
Bonda, W.L.M.; Lavergne, M.; Vasseur, V.; Brisson, L.; Roger, S.; Legras, A.; ... ; Reverdiau, P. 2021
Inflammation, oxidative stress, and protease/protease inhibitor imbalance with excessive production of proteases are factors associated with pathogenesis of the chronic obstructive pulmonary... Show moreInflammation, oxidative stress, and protease/protease inhibitor imbalance with excessive production of proteases are factors associated with pathogenesis of the chronic obstructive pulmonary disease (COPD). In this study, we report that kallikrein-related peptidase 5 (KLK5) is a crucial protease involved in extracellular matrix (ECM) remodeling and bronchial epithelial repair after injury. First, we showed that KLK5 degrades the basal layer formed by culture of primary bronchial epithelial cells from COPD or non-COPD patients. Also, exogenous KLK5 acted differently on BEAS-2B cells already engaged in epithelial-to-mesenchymal transition (EMT) or on 16HBE 14o- cells harboring epithelial characteristics. Indeed, by inducing EMT, KLK5 reduced BEAS-2B cell adherence to the ECM. This effect, neutralized by tissue factor pathway inhibitor 2, a kunitz-type serine protease inhibitor, was due to a direct proteolytic activity of KLK5 on E-cadherin, beta-catenin, fibronectin, and alpha 5 beta 1 integrin. Thus, KLK5 may strengthen EMT mechanisms and promote the migration of cells by activating the mitogen-activated protein kinase signaling pathway required for this function. In contrast, knockdown of endogenous KLK5 in 16HBE14o- cells, accelerated wound healing repair after injury, and exogenous KLK5 addition delayed the closure repair. These data suggest that among proteases, KLK5 could play a critical role in airway remodeling events associated with COPD during exposure of the pulmonary epithelium to inhaled irritants or smoking and the inflammation process. Show less
