Crosstalk between Mycobacterium tuberculosis and SARS-CoV-2 defines divergent cellular composition of murine responses

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Introduction Mycobacterium tuberculosis infects nearly a quarter of the world population, while SARS-CoV-2 has infected hundreds of millions in recent years. The cellular and genetic impact of this coinfection remains unclear. Methods Using a murine model, we studied SARS-CoV-2 superinfection during acute and chronic stages of high dose tuberculosis (TB). Results In acute TB, coinfection increased mortality associated with higher brain viral loads. During chronic TB, survival improved slightly without affecting brain infection. Interestingly, histopathology showed disorganized inflammatory responses in co-infected mice versus granuloma-like structures in TB alone. Spatial transcriptomics revealed expanded B cell populations and upregulation of immunoglobulin-associated genes, as well as an absence of distinct Tcell clusters, consistent with a relative prominence of humoral immune signatures in chronic TB. Notably, SARS-CoV-2 infection produced bronchial inflammation dominated by innate immune cells, like acute TB but unlike the infiltration of foamy macrophage during chronic TB. Discussion Overall, SARS-CoV-2 coinfection was associated with a distinct pulmonary immune landscape compared to TB alone, including differences in macrophage and lymphocyte composition and spatial organization, suggesting that coinfection may modulate the local immune response to TB and highlighting the need for further investigation into the development of vaccines and therapies targeting both pathogens.