Asymptomatic TB Transmission, Infectiousness, and Immunology

About This Grant

SUMMARY Tuberculosis (TB) is the leading cause of death due to an infectious agent. Progress in controlling the TB epidemic has fallen short of milestones and new strategies for TB control are urgently needed. Asymptomatic TB, defined as microbiological evidence of TB in people without symptoms, has recently been recognized as common (>50% of prevalent TB) and probably a significant source of M. tuberculosis (Mtb) transmission and driver of the epidemic. There are important knowledge gaps that impede interventions to target asymptomatic TB including: 1) Determining the spectrum of asymptomatic TB infectiousness and risk factors for increased infectiousness and Mtb transmission, 2) Discovering host determinants and mechanisms associated with different outcomes in the natural history of asymptomatic TB (e.g., progression to more infectious TB versus self- resolution of disease), and 3) Developing cost-effective tools to screen for people with asymptomatic TB, especially those who are most infectious or more likely to progress to infectious states. To address these knowledge gaps, this proposal will investigate infectiousness and transmission related to asymptomatic TB, disease trajectories, pathogenesis, and detection in Nairobi, Kenya, a setting with a high burden of TB. Two premises underly our proposed study: 1) Among people with AsxTB, there is a highly infectious (“superspreader”) phenotype who drive Mtb transmission; 2) The untreated clinical course of AsxTB differs between persons, includes self-resolution of TB, and is regulated by unknown clinical and immunologic factors. We will assess infectiousness (cough aerosol culture status), Mtb transmission (investigations of household and non-household contacts to identify recent transmission), immunologic pathways, and cough and biometric profiles (using personal mobile devices). Aim 1 will enroll 10,000 participants in a community-based TB prevalence survey to identify people with asymptomatic TB and symptomatic TB, estimate infectiousness based on cough aerosol culture status, and investigate household and non-household contacts for evidence of transmission using interferon-gamma dependent and independent responses. Aim 2 will follow 7500 participants for 18 months to understand the natural history of asymptomatic TB and investigate the host mechanisms associated with different TB outcomes using single-cell and bulk RNA-Seq. Aim 3 will discover personal-device based cough and biometric profiles to detect asymptomatic TB in the ambulatory setting using machine learning models. Finally, immunologic, clinical, and biometric datasets will be integrated to develop a comprehensive prediction model. This proposal’s multidisciplinary and complementary team will leverage their expertise and experience to construct a new model of asymptomatic TB pathogenesis and natural history, generate evidence on its contribution to transmission, and develop detection methods with potential for public health impacts.