Clinical epidemiological studies identified 2 classes of Mtb based on the capacity of the bacilli from index cases to be transmitted to cause infection in household contacts (HHC): Mtb-HT (high transmission) and Mtb-LT (low transmission). Chest x-ray of Mtb-HT Index Cases displayed an increased frequency of cavitary disease. Analysis of Mtb-HT and Mtb-LT in C3HeB/FeJ mice revealed remarkable differences among the 2 strains in

1. The responses elicited in AM;
2. The immunopathological patterns, with lung necrotic lesions only apparent in Mtb-HT infected mice;
3. The T cell response during the chronic phase of infection; and
4. The expression of phthiocerol dimycocerosate (PDIM), an Mtb cell envelope lipid.

These characteristics of Mtb-HT and Mtb-LT may thus link Mtb-intrinsic factors to differential regulation of the early innate immune response (the Mtb-AM interaction) that leads to the development of distinct adaptive immunity that in turn, governs the kinetics and frequency with which asymptomatic infection progresses to disease. PREDICT29 (segregates progressors vs nonprogressors), in conjunction with the ACS-COR signature (identifies individuals at a later phase of infection), enables the placement of subjects in our cohorts infected with Mtb-HT and Mtb-LT at the early phase of infection that are progressors or nonprogressors or late phase of infection. A combination of ex vivo cellular systems, singe-cell RNA-seq analysis, hi-dimensional mass cytometry, and Nanostring technology will be employed to characterize the immune response exhibited by these various subgroups.

We propose to test the following hypothesis:

3.

Memory T cells play a role in regulating infection progression