Ultra-low dose aerosol infection provides an improved murine model of tuberculosis. Ultra-low dose aerosol infection provides an improved murine model of tuberculosis

Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1-3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the mouse TB model and show that ULD infection recapitulates key features of human TB. Overall design: Whole-blood microarrays of BL6 mice measured 24 days after aerosol infection with M. tuberculosis and lung CFUs measured 26-97 days post infection, either ultra-low dose (ULD: 1-3 CFU) or conventional dose (CD: 50-100 CFU). Total 13 CD mice, 54 ULD mice and 7 unifected controls.