The respiratory tract virome: unravelling the role of viral dark matter in respiratory health and disease.

Abstract

The human respiratory tract virome is an underexplored component of the microbiome that includes eukaryotic viruses, bacteriophages and archaeal viruses. The respiratory virome represents a dynamic and heterogeneous ecosystem, shaped by host, environmental and microbial factors. Advances in metagenomic sequencing have expanded our understanding of virome composition, dynamics and potential roles in health and disease. Despite increasing interest, virome research remains fragmented and often secondary to bacteriome studies. Challenges in study design, genomic characterisation and interpretation limit consistent conclusions. This review summarises current knowledge of the respiratory virome in health and across acute and chronic respiratory diseases, including acute respiratory infection, asthma, COPD, cystic fibrosis and bronchiectasis. While each condition is distinct, they share features of airway inflammation and immune dysregulation where the virome may act as a modifier or marker. Across these syndromes, emerging evidence highlights the consistent detection of respiratory viruses including potential commensals, such as Anelloviridae, and the often-overlooked role of bacteriophages. We also discuss the concept of viral dark matter, where large proportions of sequence data remain unclassified, potentially representing novel viral taxa. Technical and conceptual challenges are evaluated, alongside recent methodological innovations such as meta-transcriptomics and viral enrichment protocols. We outline how standardised, multi-omic and longitudinal approaches are urgently needed to clarify the virome's functional role, interactions with immunity and microbial communities and its utility as a biomarker or therapeutic target.