Defining the innate-like mucosal T cell response to bacterial infection in airways disease (360G-Wellcome-211050_Z_18_A)

Exacerbations cause most morbidity, mortality and economic costs of asthma. Most are driven by infections and constitute a significant unmet clinical need, particularly in non-eosinophilic disease. The 2017 AMAZES trial showed azithromycin reduced exacerbations in severe asthma, but raises several critical questions, especially, the relevant mechanisms of action, whether anti-microbial, anti-inflammatory or immunomodulatory, remain unknown. AIMS 1.To discover the mechanisms of macrolide activity in neutrophilic asthma. 2.To define how non-typeable Haemophilus influenzae (NTHi) establishes a niche in neutrophilic airways. 3.To explore the role of mucosal associated invariant T (MAIT) cells and their ligands in infection and asthma. OBJECTIVES 1.In vitro modelling of bacteria/epithelial/immune cell interactions in NTHi-infected human airway epithelium at air-liquid interface. 2.Murine modelling of mucosal immune responses to NTHi and effects of azithromycin on pulmonary inflammation in vivo. 3.Characterisation of human airway cellular immunology and microbiology using bronchoscopy before and after azithromycin therapy to confirm the human relevance of these pathways in asthmatics with/without bacterial airway infection. This work will i) elucidate the basic immunology of host-pathogen interactions and MAIT-cell biology; ii) identify mechanisms and biomarkers key to informing and refining future human clinical trials of macrolides in airways diseases; and iii) explore the therapeutic potential of MAIT-cells.