Longitudinal study across SARS-CoV-2 variants identifies transcriptionally active microbes (TAMs) associated with Delta severity.

Emergence of new SARS-CoV-2 VOCs jeopardize global vaccine and herd immunity safeguards. VOCs interactions with host microbiota might affect clinical course and outcome. This longitudinal investigation involving Pre-VOC and VOCs (Delta & Omicron) holo-transcriptome based nasopharyngeal microbiome at taxonomic levels followed by metabolic pathway analysis and integrative host-microbiome interaction. VOCs showed enrichment of with dominance of . Interestingly with superiority of and , were highlights of Delta VOC rather than Omicron. Common species comprising the core microbiome across all variants, reiterated the significance of in Delta, and its association with metabolic pathways enhancing inflammation in patients. Microbe-host gene correlation network revealed , , and modulating immune pathways, which might augment clinical severity in Delta. Importantly, opportunistic species of , , , and were abundant in Delta-mortality. The study establishes a functional association between elevated nasal pathobionts and dysregulated host response, particularly for Delta.