Bacterial and host determinants of progression, manifestations and consequences of TB

ABSTRACT - PROJECT 1 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 was associated with greater risk of progression to disease and more cavitation on chest X-ray. As regards host heterogeneity, we posit that risk of signature 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. As regards short-and long- term risk of progression, in Brazil, we characterized a transcriptional signature PREDICT29 tied to the immune response that predicted progression to TB. We will use the household contact model in a prospective cohort in Uganda and retrospective cohorts in Uganda and Brazil to partition the risk of infection with Mtb-HT between immunopathology of the index case (eg cavitation and subsequent lung damage), greater force of infection for HHC, the modifying effects of PREDICT29 and co-morbidities, and increased risk of progression along the spectrum from LTBI to TB. Specific Aims are to determine the impact of Mtb strain phenotype (eg Mtb-HT v Mtb-LT) and host heterogeneity (risk of progression signatures, co-morbidities) on: 1. The distribution of stages of Mtb infection and disease in exposed HHC: the proportion of MTBI that express PREDICT29, a risk of progression signature; ACS-COR, an inflammatory signature; subclinical TB and active TB; 2. The risk and timing of progression from MTBI to TB and 3. The extent and nature (eg cavitation) of pulmonary disease in TB index cases; the duration of inflammation; and the consequent impairment in pulmonary function. 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 from well-characterized populations that will allow determination of the immunologic basis for the findings in this Project 1; and with Projects 3 in providing clinical Mtb isolates known to differ in transmission and pathogenesis for study of tolerance.