Fig. 6: Inhibition of the TcrXY TCS attenuates Mtb survival during chronic infection and accelerates bacterial clearance with front-line anti-TB agents.

a Mtb survival in the lungs and spleens of chronically-infected mice upon CRISPRi-mediated tcrX silencing. Female C57BL/6 mice were co-infected with <500 CFU of a 1:1 mix of Mtb H37Rv and CRISPRi-tcrX. Mice were rested for 4 weeks to establish a wild-type like chronic infection, before CRISPRi-mediated TcrX depletion by doxycycline (doxy) administration in mouse chow (2000 ppm). Each time point represents the mean recovered CFU from each organ from six mice, with error bars denoting SD. Statistical analysis was performed using an unpaired two-tailed t-test at week 10. b Mtb fitness in the lungs and spleens of chronically-infected mice upon CRISPRi-mediated tcrX silencing. Competitive index (CI) from (a) was calculated from recovered CFU counts for each strain, and normalised to the onset of doxy administration. Each point is the CI from each mouse organ, with the median of each group denoted by a horizontal line. c, Mtb clearance from the lungs of chronically-infected mice treated with rifampicin (RIF) and isoniazid (INH). Female C57BL/6 mice were co-infected with <500 CFU of a 1:1 mix of Mtb H37Rv and CRISPRi-tcrX. Mice were rested for 4 weeks to establish a wild-type like chronic infection, before treatment with RIF and INH (0.1 mg/mL in drinking water). CRISPRi-mediated TcrX depletion was induced by doxy administration in mouse chow (2000 ppm) (with doxy). In parallel, a control group received the same base mouse feed composition without doxy (no doxy). Each time point represents the mean recovered CFU from each organ from six mice, with error bars denoting SD. Statistical analysis was performed using an unpaired two-tailed t-test at 10 weeks of treatment. d Mtb fitness in the lungs of chronically-infected mice treated with RIF and INH upon CRISPRi-mediated tcrX silencing. Competitive index from (c) was calculated from recovered CFU counts for each strain, and normalised to the onset of doxy administration. Each point is the CI from each mouse lung, with the median of each group denoted by a horizontal line. Source data are provided as a Source Data file.