July 11, 2019

Principal Investigators:

Timothy Sterling, MD
Bruno Andrade
Thomas Hawn

Critical to preventing tuberculosis (TB) is a better understanding of the protective and predisposing factors for progression from M. tuberculosis infection to TB disease. Our group has reported a peripheral blood correlate of risk (COR) transcriptional signature that identified persons with incipient (asymptomatic) TB who progressed to active (symptomatic)TB within 12 months, and also human genetic polymorphisms in a DNA sensor gene region (PYHIN1-IFI16-AIM2) associated with TB risk. We seek to evaluate the immunogenetic and epidemiologic risk factors for active and incipient TB in a Brazilian cohort of HIV-negative and HIV-positive close TB contacts, to identify host pathways associated with protection against TB (for future vaccines), and to identify persons who would benefit from TB preventive therapy.

Drs. Timothy Sterling, Bruno Andrade (Instituto Brasileiro para Investigação da Tuberculose (IBIT), Salvador, Brazil), and Thomas Hawn (University of Washington) received a 5 year R01 grant from the National Institutes of Health entitled, “Immunogenetic predictors of active and incipient TB in HIV-negative and -positive close TB contacts” (R01AI147765). This was in response to PAR-16-254, "Mechanisms of Mycobacterial-Induced Immunity in HIV-Infected and Uninfected Individuals to Inform Innovative Tuberculosis Vaccine Design (R01)." Total funding awarded for the 5-year project is $3.6 million, with subcontracts to the Fundação para o Desenvolvimento Científico e Tecnológico em Saúde (FIOTEC; Brazil), the University of Washington, and the University of Cape Town (South Africa). Collaborators include Spyros Kalams, Simon Mallal, Mark Pilkinton, and Peter Rebeiro at Vanderbilt; Valeria Rolla, Afranio Kritski, Marcelo Cordeiro Santos, Solange Cavalcante, Cristina Lourenco, and Ricardo Khouri in Brazil; Javeed Shah at the University of Washington; and Mark Hatherill, Thomas Scriba, and Stanley Kimbung at the University of Cape Town.

This grant project seeks to understand the protective and predisposing factors for progression from M. tuberculosis infection to TB disease. The group has previously reported a peripheral blood correlate of risk (COR) transcriptional signature that identifies persons with incipient (asymptomatic) TB who subsequently progress to active (symptomatic) TB within 12 months, and also human genetic polymorphisms in a DNA sensor gene region (PYHIN1-IFI16-AIM2) associated with TB risk. In this project, the group will evaluate innate immune responses in macrophages and their correlates with human genetic polymorphisms, acquired immunity to M. tuberculosis, 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. This work may identify host pathways associated with protection against TB (for future host-directed therapies and vaccines), and to identify persons infected with M. tuberculosis who would benefit most from TB preventive therapy.

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