The human oral and airway viral genome catalog from metagenomes enables virome characterization informing respiratory health.

BACKGROUND: Viral communities of the upper aerodigestive tract represent an important component of the human microbial ecosystem but remain poorly characterized due to the limited availability of habitat-specific reference resources. METHODS: We integrated 19,997 public and 2,673 newly sequenced oral and airway metagenomes to establish the Oral and Airway Viral Genome Catalogue (OAVGC). Viral genomes were reconstructed and characterized through taxonomic assignment, prokaryotic host prediction, functional annotation, and assessment of putative antibacterial activity. Our prospective longitudinal aging cohort, alongside 5 in-house datasets and publicly cohorts, were analyzed to investigate associations between airway virome profiles and respiratory health. FINDINGS: The OAVGC comprised 141,459 high-quality viral genomes (completeness ≥90%) clustered into 68,708 viral operational taxonomic units (vOTUs). Approximately half of these viruses and families are previously undescribed, with independent cross-cohort detection and PCR assays providing additional support for their occurrence. Across multiple respiratory infection cohorts, the virome exhibited convergent diversity reductions and compositional signatures. In the prospective cohort, the baseline airway virome was correlated with host lung function and geriatric health scores. Virome-based machine learning classifiers demonstrated potential for predicting the future occurrence of upper respiratory tract infections up to 12 months in advance, outperforming bacteriome-based models in our prediction analyses. CONCLUSIONS: The OAVGC provides an unprecedented genomic and functional resource for investigating the ecological and clinical associations of the oral-airway virome, revealing its potential impact on respiratory health and capacity to predict future infections. FUNDING: National Natural Science Foundation of China (82341113) and National Key R&D Program of China (2022YFA1304303).