Apparent Sterilizing Immunity In Bcg-Immunized Mice Challenged With An Ultra-Low Dose Of Mycobacterium Tuberculosis

Abstract Tuberculosis (TB) is a highly heterogeneous disease that develops in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). To improve upon the standard experimental mouse model, we infected mice with an ultra-low Mtb dose (ULD), consisting of 1-3 founding bacteria, which reflects the physiologic inoculum of humans. These mice exhibited a broad range of outcomes, with bacterial burdens ranging from <10 to ~106 CFUs in individual lungs. Furthermore, they exhibited well-circumscribed granulomas that share features with human granulomas. To monitor outcomes in live mice, we identified a blood RNA signature that correlated with lung bacterial burdens. Remarkably, this mouse-derived signature predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Given these improvements in the mouse model, we wondered whether ULD infection would provide a better platform for assessing vaccine-induced immunity. We now report that BCG-immunized mice, compared to unimmunized controls, exhibited a lower percentage of infected mice at late timepoints after ULD Mtb challenge. Interestingly, this difference was not observed at earlier timepoints. Taken together, these results suggest that some BCG-immunized mice, upon subsequent Mtb aerosol challenge, are capable of eradicating their initial infection, a finding that has not previously been observed in the TB mouse model. We are currently developing methods to verify initial infection prior to potential clearance and are also investigating immune correlates of protection.