Abstract Tuberculosis (TB) disease remains the leading cause of mortality from an infectious disease globally, with an estimated 1.6 million deaths in 2021. TB is caused by infection with Mycobacterium tuberculosis (Mtb), resulting in variable outcomes from asymptomatic latent infection to clinical TB disease. However, most individuals exposed to Mtb never develop clinical disease. We hypothesize that host factors, including metabolic pathways, determine the outcome of Mtb infection. Based on prior data from human cohorts we observed an association between impaired tyrosine metabolism and progression to TB disease. We then reanalyzed a public dataset of Mtb-infected monocyte derived dendritic cells (DCs) and found that stimulation with either live or heat-inactivated Mtb resulted in downregulation of FAH (fumarylacetoacetate hydrolase), which encodes the last enzyme in the tyrosine catabolism pathway. Next, we used gene editing of FAH in conditionally immortalized myeloid progenitors (CIM) from mice to test whether downregulation of the FAH gene is associated with higher susceptibility to Mtb. We generated three independent fah-edited CIM lines, with two lines showing editing efficiency above 90%. We infected wildtype and fah-edited CIMs with an H37Rv-lux Mtb strain and detected significantly higher Mtb growth in fah-edited CIMs compared to wildtype CIMs (p=0.004). We also successfully optimized CRISPR in primary human monocyte derived DCs and macrophages to define the role of FAH during infection in physiologically relevant myeloid cell types. Our data suggest that FAH deletion compromises immune control of Mtb. We are currently exploring the immunoregulatory roles of FAH during Mtb infection, including inflammasome activation.