Historically, TB has been characterized as a two-stage process – infection and disease. It now is clear that infection and importantly the likelihood once infected of progressing to TB is heterogeneous and varies with time. ​​​​We propose now to address in human studies how bacterial and host heterogeneity modify the distribution of stages of TB infection following close contact with a TB case, the risk of progression and the manifestations and sequelae of TB disease. Historically, TB has been characterized as a two-stage process – infection and disease. It now is clear that infection and importantly the likelihood once infected of progressing to TB is heterogeneous and varies with time. We propose now to address in human studies how bacterial and host heterogeneity modify the distribution of stages of TB infection following close contact with a TB case, the risk of progression and the manifestations and sequelae of TB disease. On the bacterial side, Mtb strains from index cases could be dichotomized into high transmission (Mtb-HT) and low transmission (Mtb-LT) based on the proportion of exposed household contacts that were TST+. Mtb-HT has been associated with a greater risk of progression to disease and more cavitation on chest x-ray. In regards to host heterogeneity, we posit that risk signatures are a proxy for intrinsic differences in the host immune response to Mtb. In South Africa, the ACS- COR signature was a good correlate of PET-CT scan findings of subclinical TB. In terms of short-and long- term risk of progression, in Brazil, we characterized PREDICT29, a transcriptional signature tied to the immune response that predicted progression to TB.

Scientific Aims

These studies could permit individualized approaches to diagnosis, targeting of preventive therapy, and treatment of active TB. They synergize with Project 2 and the Clinical Core in providing PBMC and BAL samples from well-characterized populations that will allow determination of the immunologic basis for the findings in this Project 1, and with Project 3 in providing clinical Mtb isolates known to differ in transmission and pathogenesis for the study of tolerance.