Immunological roads diverged: mapping tuberculosis outcomes in mice

The journey from phenotypic observation to causal genetic mechanism is a long and challenging road. For pathogens like Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), host–pathogen coevolution has spanned millennia, costing millions of human lives. Mammalian models can systematically recapitulate host genetic variation, producing a spectrum of disease outcomes. Leveraging genome sequences and deep phenotyping data from infected mouse genetic reference populations (GRPs), quantitative trait locus (QTL) mapping approaches have successfully identified host genomic regions associated with TB phenotypes. Here, we review the ongoing optimization of QTL mapping study design alongside advances in mouse GRPs. These next-generation resources and approaches have enabled identification of novel host–pathogen interactions governing one of the most prevalent infectious diseases in the world today.