The upregulation of the ESX-1 secretion system at both the RNA and the protein level in M. bovis AF2122/97 with the observed upregulation of DNA-sensing pathways and the NLRP3/IL-1β pathway in M. bovis AF2122/97-infected macrophages shows how the expression level of virulence factors between MTBC species, rather than their presence or absence, can drive divergent host responses and influence infection outcome overall. Here, NLRP3 is linked to infection.