Timothy Sterling, MD, professor of Medicine in the division of Infectious Diseases at Vanderbilt University Medical Center, has received a five-year, $5.7 million grant from the National Institute of Allergy and Infectious Diseases to investigate how Mycobacterium tuberculosis spreads from person to person.
Tuberculosis reclaimed its position as the world’s deadliest infectious disease in 2023, surpassing COVID-19. The World Health Organization estimates that 10.7 million people fell ill with TB in 2024 and 1.23 million died from the disease.
Scientists lack complete understanding of the biological factors that drive TB transmission, including those encoded in the pathogen itself. Sterling’s project aims to help fill that gap by studying TB transmission in the large, well-characterized Regional Prospective Observational Research in Tuberculosis-Brazil cohort, or RePORT-Brazil. Sterling has been among RePORT-Brazil’s principal investigators since its founding in 2013. Researchers aim by next year to expand the cohort to include some 2,000 persons with TB and 4,000 of their close contacts.
The team will use whole genome sequencing to analyze M. tuberculosis isolates from TB patients and identify genetic variants associated with increased transmissibility. They’ll also examine immune responses in close contacts of TB patients to better understand the full spectrum of outcomes following exposure to TB — including infections that don’t trigger the standard immune markers clinicians currently use for diagnosis.
Additional lab methods such as bacterial physiological profiling and reverse bacterial genetics will seek to expose mechanisms underlying transmission outcomes.
“We know that some strains of TB bacteria appear to spread more readily than others, but we don’t fully understand why,” said Sterling, who holds the David E. Rogers Professorship. “By combining advanced genomic analysis of the bacterium with detailed immunological profiling of close contacts, we hope to identify the bacterial and host factors that predict transmission. This knowledge could ultimately help us develop better tools for interrupting the spread of this disease.”
The project in part seeks to address the emerging recognition that subclinical TB — active disease without symptoms — may account for as much as half of all TB cases. These individuals may unknowingly contribute to transmission in ways not captured by current surveillance methods. Subclinical TB is not to be confused with latent TB infection — a nonactive, noninfectious condition which is estimated to affect one-quarter of the world’s population.
Using data from both the bacterial and human sides of the transmission equation, Sterling and team will develop prediction models incorporating pathogen genetics, patient characteristics and epidemiological factors. If successful, these models could inform the development of diagnostic tools to identify highly transmissible strains and guide public health interventions.
Joining Sterling in leading the project are Bruno de Bezerril Andrade, MD, PhD, who recently joined Johns Hopkins University in Baltimore from the Oswaldo Cruz Foundation (Fiocruz) in Salvador, Brazil, and Sarah Fortune, MD, of Harvard University in Boston. Additional collaborators include Qingyun Liu, PhD, of the University of North Carolina, Chetan Seshadri, MD, of the University of Washington, and Leonardo Barreto of Fiocruz in Rio de Janeiro. VUMC collaborators include Gustavo Amorim, PhD, Peter Rebeiro, PhD, MHS, Marina Figueiredo, DVM, MS, Cindy Nochowicz, Hilary Vansell Riley, MMCH, and Erin Graves McKee, BSN, MPH.
The project is supported by National Institutes of Health award R01AI194298.
