PROJECT SUMMARY Recent studies from our group have reported a peripheral blood correlate of risk (COR) transcriptional signature that identified individuals with incipient (asymptomatic) TB who progressed to active (symptomatic) TB disease within 12 months. We have also identified human genetic polymorphisms in a DNA sensor gene region (PYHIN1-IFI16-AIM2) associated with TB risk in Brazilian close TB contacts. Both the COR and PYHIN1-IFI16-AIM2 include interferon stimulated genes (ISGs). We hypothesize that there are immunogenetic pathophysiologic factors associated with incipient TB and progression to active TB. To address this question, we will evaluate innate immune responses in macrophages and their correlates with human genetic polymorphisms, acquired immunity to M. tuberculosis (Mtb), and epidemiologic factors associated with the risk of incipient and active TB. These studies will be performed in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort, which includes culture-confirmed TB cases and their close contacts in racially and ethnically diverse Brazil. Close contacts are followed for 2 years to identify development of TB disease; most persons do not receive or complete preventive therapy, so 40 new culture- confirmed TB cases are expected among 2,000 close contacts, ~45% of whom will be infected with Mtb. Epidemiologic and clinical data, peripheral blood mononuclear cells (PBMC), RNA from whole blood (PAXgene), and genomic DNA are available from all close contacts at baseline, 6 months, and at TB diagnosis. Identification of these immunogenetic risk factors (including HIV) will illuminate host pathways associated with both a) immunity to Mtb, which could be translated into host-directed and vaccine therapies, and b) progression to TB—to identify persons who would benefit from TB preventive therapy.