Non-typeable Haemophilus influenzae airways infection: the next treatable trait in asthma?

Asthma is a complex, heterogeneous condition characterised by bronchial hyperreactivity and airways inflammation which affects over 350 million people globally. A subset display marked airway neutrophilia, associated with worse lung function, higher morbidity and poor response to treatment. In these individuals, recent metagenomic studies identify persistent bacterial infection, particularly with non-encapsulated strains of the gram-negative bacterium Haemophilus influenzae. Here we review knowledge of non-typeable H. influenzae (NTHi) in the microbiology of asthma, the immune consequences of mucosal NTHi infection, various immune evasion mechanisms, and the clinical implications of NTHi infection for phenotyping and targeted therapies in neutrophilic asthma. Airway neutrophilia is associated with production of neutrophil chemokines and proinflammatory cytokines in the airways including IL-1, IL-6, IL-8, IL-12, IL-17A, and TNF. NTHi adheres and invades the lower respiratory tract epithelium inducing the NLRP3 and AIM2 inflammasomes. NTHi reduces expression of tight-junction proteins impairing epithelial integrity, and can persist intracellularly. NTHi interacts with rhinoviruses synergistically via upregulation of ICAM-1 and promotion of a neutrophilic environment to which NTHi is adapted. We highlight the clinical relevance of this emerging pathogen, its relevance for the efficacy of long-term macrolide therapy in airways diseases, identify important unanswered questions, and propose future directions for research