Uncovering lung virome signatures of COPD severity and acute exacerbations in longitudinally sampled AERIS cohort

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is increasingly recognized as a complex disorder in which microbial communities may modulate disease progression and exacerbation risk. We investigated the contribution of the respiratory virome to disease severity and acute exacerbations in COPD using a comprehensive longitudinal dataset that simultaneously profiled eukaryotic viruses and bacteriophages across deeply phenotyped COPD subtypes. Sputum samples were collected longitudinally from 98 patients with a history of frequent exacerbations at the University Hospital Southampton between 2011 and 2013 as part of an observational cohort study. To characterize the lung virome in these patients, we analyzed 520 samples using high-throughput metagenomic sequencing. Viral genomes were identified in 424 of these samples with state-of-the-art bioinformatic methods. Ubiquitous anelloviruses exhibited a significant increase in their genus diversity with exacerbation events. Rhinoviruses were confirmed as primary viral triggers of flare-ups. Bacteriophage richness declined with increasing COPD severity, characterized by continuous impaired lung capacity and elevated airway obstruction. In addition, we detected Haemophilus -infecting phages carrying virulence factors or anti-phage defense systems in lungs with increased Haemophilus bacterial loads, suggesting that these phages are associated with bacterial fitness and microbial dysbiosis. We further demonstrated high inter-individual variability in virome composition, with exacerbation events consistently associated with more pronounced dysbiosis. Despite inherent challenges of sputum-based virome profiling, we performed, to our knowledge, the first longitudinal characterization of the COPD virome and reported underlying stability trends. Our findings emphasize that a deeper understanding of respiratory virome dynamics holds promise for identifying novel COPD biomarkers and developing targeted therapeutic strategies.