Although preventing infection by Mycobacterium tuberculosis (Mtb) is paramount for controlling the tuberculosis (TB) epidemic, transmission in endemic settings is poorly understood. Across communities in high burden settings, there is variability in TB prevalence in the form of spatial clusters or “environmental hotspots”. Heterogeneity is also present in the infectiousness of patients with TB, leading to the concept of “individual superspreaders,” who are responsible for the majority of Mtb transmission events. The overall objective of this project is to develop novel interventions to interrupt Mtb transmission by discovering the primary drivers at the individual and community levels through evaluations of hotspots and superspreaders. We previously developed a novel Mtb cough aerosol sampling system (CASS) and a digital cough signature assessment platform and discovered immunogenetic factors associated with resistance and susceptibility to Mtb infection and TB disease. In 2015, the Kenya National TB Program, conducted a nationwide population-based TB survey, that found a high burden of TB with wide variation between surveyed communities. We now propose to investigate TB prevalence within 10 previously surveyed Nairobi neighborhoods (with varying TB burdens), develop novel tools for identifying superspreaders including aerobiology and immunogenetic profiling, and investigate biomarkers of recent transmission among household contacts (HHCs). We hypothesize that highly infectious individuals have unique digital cough and immunologic signatures, and that their HHCs have a higher frequency of persistently positive interferon-gamma release assays (IGRAs), specific transcriptional profiles, and higher rate of progression to TB disease. We hypothesize that neighborhoods with stably high TB prevalence rates are associated with demographics skewed to young men, high in-migration, decreased healthcare access, and poorly ventilated community spaces. By using innovative methods, we will gain insights into temporal trends of TB prevalence in small areas, identify factors associated with high prevalence, and develop tools to identify individuals responsible for a disproportionate amount of TB transmission. Knowledge from this study will enable targeting of resources to improve TB control.