Host-strain compatibility influences transcriptional responses in Mycobacterium tuberculosis infections

Tuberculosis, caused by Mycobacterium tuberculosis, is a leading cause of infectious mortality and affects humans and other mammals. Understanding the drivers of its host-specificity shapes the landscape of infectivity, which could potentially inform strategies for tuberculosis management. We hypothesise that host-strain compatibility influences infection outcome and we aim to reveal bacteria and host specific transcriptional responses during in vitro infections. We infected human and bovine cell lines with two human-associated M. tuberculosis strains from lineages 5 and 6, as well as two animal-associated strains (Mycobacterium bovis and the Chimpanzee bacillus), and quantified infection ratios, cell death, and transcriptional responses. By integrating those data from different compatibility combinations, we identified global transcription profiles associated with strain-host compatibility. Our results show that the most compatible host-strain combinations had higher infection rates, and different transcriptional patterns than low-compatibility infections. Both hosts had similar transcriptional responses to their most compatible strains, upregulating pathways related with increased cell proliferation. Host proliferation could potentially favour bacterial growth, explaining the success of the strain in its corresponding host. Conversely, both hosts responded to non-associated strains with defence related transcriptional patterns, among other pathways, supporting their lower success in the non-associated host. Finally, we revealed bacteria and host-specific expression patterns in molecules implicated in immune response and inflammation through the eicosanoid pathway. In conclusion, we confirmed that bacteria-host compatibility determines common transcriptional responses, but also specific responses that depend on the infecting strain. This study enhances the understanding of host-specific adaptation mechanisms in M. tuberculosis.