The Human Respiratory Virome in Health and Disease: Interactions, Dysbiosis, and Methodological Challenges

The human respiratory virome is an underexplored component of the microbiome that includes diverse DNA and RNA viruses such as eukaryotic viruses, bacteriophages, and archaeal viruses. Recent advances in metagenomics have revealed the complexity and dynamic nature of the human respiratory virome, which interacts closely with the host and the bacterial microbiome to influence respiratory health and disease. In healthy individuals, the virome is characterized by low biomass and high temporal variability, with <i>Anelloviruses</i> predominant in the upper airways, whereas <i>Streptococcus</i> phages and herpesviruses are most commonly detected in the lower airways. Common respiratory viruses, such as <i>respiratory syncytial virus</i>, <i>human rhinovirus</i>, and <i>influenza A virus</i>, can persist after acute infection and modulate host immunity. The respiratory virome also plays a significant role in chronic respiratory diseases. Despite its importance, research on the respiratory virome is hampered by technical challenges, including low viral abundance and limited reference databases. This review summarizes current understanding of the composition and determinants of the respiratory virome in healthy individuals, describes its interactions with the host and respiratory microbiota, including the potential modulatory roles of bacteriophages, outlines virome alterations in respiratory diseases, examines methodological challenges, and highlights potential clinical applications and future research directions.