Research in the MCKINNEY LAB is focused on the mechanistic basis of Mycobacterium tuberculosis persistence in the context of host immunity and antimicrobial therapy. Our research covers four areas: COUNTER-IMMUNITY. Host immunity is usually sufficient to contain M. tuberculosis infection, but not to eradicate infection. We seek to identify the mechanisms that M. tuberculosis uses to evade or counter the impact of the host immune response. IN VIVO METABOLISM. In recent years, central metabolism has emerged as an attractive target for antimicrobial drug discovery. We seek to identify the catabolic and anaplerotic pathways that are required for M. tuberculosis growth and persistence during infection of the mammalian host. ANTIBIOTIC TOLERANCE. Tuberculosis is notoriously refractory to antimicrobial therapy. We seek to understand the mechanistic basis of M. tuberculosis persistence in the antibiotic-treated host, and the epigenetic control of cell-to-cell variation in antibiotic sensitivity. CELL CYCLE DYNAMICS. M. tuberculosis is also notorious for its unusually slow intrinsic growth rate in vitro and in vivo (the minimum population doubling time is about 20 hours in either environment). We seek to understand why M. tuberculosis grows so slowly and to identify the physiologic adaptations that are required for slow growth. Our experimental approaches include molecular genetics, tissue culture and animal infection models, computational modeling, mass spectrometry, microfluidics, and time-lapse fluorescence microscopy.