Fatty acids as friend or foe: contribution of vacj and vacj and fadl outer membrane proteins to nontypable haemphilus influenzae interplay with the human airways

Abstract

Backgrounds Nontypable Haemophilus influenzae (NTHi) is an opportunistic pathogen associated to exacerbations of chronic obstructive pulmonary disease (COPD), a progressive irreversible airflow limitation accompanied by emphysema, fibrosis, inflammation and mucus hypersecretion. Fatty acid metabolites are key molecular mediators of COPD. Thus, NTHi may encounter free fatty acids in its colonizing niche. NTHi contains the fadL gene, encoding a fatty acid outer membrane (OM) transporter, but lacks a complete b-oxidation pathway, and a bactericidal effect of polyunsaturated fatty acids has been described for this pathogen. Conversely, NTHi contains all fatty acids and phospholipids (PL) biosynthetic genes, and vacJ/mlaA-mlaBCDEF, an intermembrane PL trafficking system serving to prevent PL accumulation in the OM, being VacJ/MlaA an OM lipoprotein. Mla mutant suppression by phospholipases (Pld) may result in production of free fatty acids that, in turn, could be taken by FadL, therefore functionally relating VacJ and FadL. In NTHi, Plds distribution is unknown, fatty acids uptake has not been shown, and VacJ contributes to virulence. We hypothesize that fatty acids uptake may not be fruitful to NTHi; also, VacJ and FadL may modulate bacterial fatty acid composition and/or interaction dynamics with exogenous hydrophobic molecules. Objectives Analysis of FadL and VacJ contribution to NTHi-host interplay. Methods NTHi vacJ and fadL mutant strains were generated and characterized in terms of growth, lipidic composition, lipid A structure, resistance to hydrophobic antimicrobials, airway infection in vitro and in vivo. Conclusions The results obtained highlight the importance of maintaining the bacterial surface integrity as a whole during NTHi airway infection