Glucose catabolism by respiration assisted fermentation leading to acetate production has a key contribution to chronic patient airway infection by Haemophilus influenzae

Abstract

Many chronic pulmonary diseases have aspects of their pathogenesis influenced by pathogens. Haemophilus influenzae (Hi) infection and chronic obstructive pulmonary disease (COPD) are an example of such an association where a bidirectional relationship between COPD and the bacteria impacts pathogenesis. The COPD airways present increased concentrations of glucose driving proliferation of bacteria able to use glucose as a carbon source. Hi uses a specialized type of glucose catabolism termed respiration assisted fermentation with a respiratory chain that alleviates redox imbalances due to incomplete glucose oxidation. We hypothesise that Hi glucose catabolism is a pathoadaptative trait playing a pivotal role in COPD infection. To find out whether this is true, we engineered bacterial mutant strains unable to produce acetate, formate or succinate, main products of Hi glucose metabolism, by inactivation of the ackA, pflA and frdA genes. Mutant phenotyping was performed by analysis of bacterial morphology, proliferation, fatty acid content, metabolic end products, gene expression profiling, and murine lung infection. Inactivation of the ackA gene impaired acetate production leading to slow bacterial growth, increased myristic and decreased palmitoleic acid content, and production of lactate under low oxygen tension. The mutation also caused bacterial attenuation in vivo. This information has important implications for developing non-antibiotic therapeutics against bacterial infections, given that airway glucose homeostasis modifying drugs could help preventing chronic lung disease exacerbations.