NTHi Killing Activity is Reduced in COPD Patients and is Associated with a Differential Microbiome

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by airway obstruction and inflammation. Non-typeable Haemophilus influenzae (NTHi) lung infections are common in COPD, promoting frequent exacerbations and accelerated lung function decline. The relationship with immune responses and NTHi are poorly understood. Herein, we comprehensively characterized the respiratory microbiome and mycobiome of patients while investigating microbial dynamics and host immune changes attributable to anti-NTHi activity.Mild-to-moderate COPD patients encompassing frequent (P-FE) and infrequent exacerbators (P-IE) and healthy volunteers (HV) were enrolled. Microbial composition, proteomics and anti-NTHi killing activity was analyzed using bronchoalveolar lavage fluid (BALF). Antigen-antibody titers in sera to COPD pathogens were determined using a multiplex assay. Differential abundance analysis revealed an enrichment of Actinobacteria and Bacteroidetes in the BALF of HV and COPD subjects respectively, with limited differences seen between P-FE vs. P-IE. Significant differences in the IgA titer response were observed against NTHi antigens in COPD vs. HV. Notably, there was also significantly greater killing activity against NTHi in BALF from COPD vs. HV subjects. Stratification of COPD patients by killing activity identified unique microbial and protein signatures wherein Firmicutes, Actinobacteria and haptoglobin were enriched in patients with killing activity. We report that host immune responses characterized by antibody-mediated NTHi-killing are asssociated with microbiome changes in mild-to-moderate COPD. This is suggestive of a potential link between microbiome and immune activity against NTHi in the context of COPD pathogenesis even at this disease stage.