Haemophilus influenzae glucose catabolism leading to production of the immunometabolite acetate has a key contribution to the host airway-pathogen interplay.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and impaired airway immunity, which provides an opportunistic platform for nontypeable (NTHi) infection. Clinical evidence supports that the COPD airways present increased concentrations of glucose, which may facilitate proliferation of pathogenic bacteria able to use glucose as a carbon source. NTHi metabolizes glucose through respiration-assisted fermentation, leading to the excretion of acetate, formate and succinate. We hypothesised that such specialized glucose catabolism may be a pathoadaptive trait playing a pivotal role in NTHi airway infection. To find out whether this is true, we engineered and characterized bacterial mutant strains impaired to produce acetate, formate or succinate by inactivating the , and genes, respectively. While inactivation of the and genes only had minimal physiological effects, inactivation of the gene affected acetate production and led to reduced bacterial growth, production of lactate under low oxygen tension, and bacterial attenuation . Moreover, bacterially produced acetate was able to stimulate the expression of inflammatory genes by cultured airway epithelial cells. These results back the notion that the COPD lung supports NTHi growth on glucose, enabling production of fermentative endproducts acting as immunometabolites at the site of infection. Thus, glucose catabolism may contribute not only to NTHi growth but also to bacterially driven airway inflammation. This information has important implications for developing non-antibiotic antimicrobials, given that airway glucose homeostasis modifying drugs could help preventing microbial infection associated to chronic lung disease.