Immunological roads diverged: mapping tuberculosis outcomes in mice

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, remains a global health crisis, diagnosed in ten million individuals and claiming 1.3 million lives annually.To explore the wide spectrum of TB disease complexes among diverse individuals, a comprehensive toolbox of next-generation mammalian and bacterial genetic tools is required.Classical breeding strategies (backcrosses, F2 intercrosses, congenics, consomics) and modern genetic reference populations (BXD, Collaborative Cross, Diversity Outbred) model a spectrum of TB outcomes and have successfully identified several host loci that modulate disease phenotypes.Deep host–pathogen phenotyping and genome sequencing efforts support the ongoing optimization of quantitative trait locus (QTL) mapping study design to identify novel host–microbe interactions that govern TB outcome. 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. 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.