ABSTRACT
Glucocorticosteroids are used as a main treatment to reduce airway inflammation in people with asthma who suffer from neutrophilic airway inflammation, a condition frequently associated with Haemophilus influenzae colonization. Here we show that glucocorticosteroids have a direct influence on the behavior of H. influenzae that may account for associated difficulties with therapy. Using a mouse model of infection, we show that corticosteroid treatment promotes H. influenzae persistence. Transcriptomic analysis of bacteria either isolated from infected mouse airway or grown in laboratory medium identified a number of genes encoding regulatory factors whose expression responded to the presence of glucocorticosteroids. Importantly, a number of these corticosteroid-responsive genes also showed elevated expression in H. influenzae within sputum from asthma patients undergoing steroid treatment. Addition of corticosteroid to H. influenzae led to alteration in biofilm formation and enhanced resistance to azithromycin, and promoted azithromycin resistance in an animal model of respiratory infection. Taken together, these data strongly suggest that H. influenzae can respond directly to corticosteroid treatment in the airway potentially influencing biofilm formation, persistence and the efficacy of antibiotic treatment.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Drug Resistance, Bacterial/drug effects , Glucocorticoids/metabolism , Haemophilus Infections/microbiology , Haemophilus influenzae/drug effects , Haemophilus influenzae/physiology , Animals , Asthma/complications , Asthma/drug therapy , Azithromycin/pharmacology , Biofilms/growth & development , Disease Models, Animal , Gene Expression Profiling , Glucocorticoids/therapeutic use , Humans , Mice , Sputum/microbiologyABSTRACT
During the past 50 years, the prevalence of asthma has increased and this has coincided with our changing relation with microorganisms. Asthma is a complex disease associated with local tissue inflammation of the airway that is determined by environmental, immunological, and host genetic factors. In a subgroup of sufferers, respiratory infections are associated with the development of chronic disease and more frequent inflammatory exacerbations. Recent studies suggest that these infections are polymicrobial in nature. Furthermore, there is increasing evidence that the recently discovered asthma airway microbiota may play a critical role in pathophysiological processes associated with the disease. Here, we discuss the current data regarding a possible role for infection in chronic asthma with a particular focus on the role bacteria may play. We discuss recent advances that are beginning to elucidate the complex relations between the microbiota and the immune response in asthma patients. We also highlight the clinical implications of these recent findings in regards to the development of novel therapeutic strategies.