Distinct and synergistic immunological responses to SARS-CoV-2 and <i>Mycobacterium tuberculosis</i> during co-infection identified by single-cell-RNA-seq

Abstract COVID-19 and tuberculosis (TB) exhibit similar symptomatic presentation, clinical parameters and co-diagnosis increases COVID-19 mortality yet there is limited understanding of the mechanisms underlying their immunopathogenic interactions. Here we show by single-cell RNA-sequencing of 18,990 cells from whole blood uninfected or infected with Mycobacterium tuberculosis ( Mtb ), SARS-CoV-2, or both pathogens, their shared, distinct, and synergistic immunological interactions. The greatest transcriptional divergence occurred within monocytes and two neutrophil subsets at early timepoints of infection. Co-infection had the greatest synergistic effect 24 hours post-infection including enrichment of IFN-γ and TNF production, whilst 96 hours post-infection Mtb , SARS-CoV-2 and co-infection shared considerable pathway overlap. SARS-CoV-2 infection alone resulted in widespread cell death 96 hours post-infection, whilst Mtb and co-infection had enhanced cell survival at 96 hrs, sharing negative regulation of extrinsic apoptosis. Our findings elucidate potential pathways for targeted host-directed therapies, which is particularly crucial for settings where these pathogens are now endemic.