Population Genomics-Guided Dissection of the Bacterial Genetic Basis of Tuberculosis Transmissibility

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) is one of the most persistent pathogens that has been transmitted within the human population for millennia. The convention of this field has largely focused on understanding the mechanisms of the virulence genes that make Mtb pathogenic. However, the bacterial genetic basis underlying tuberculosis (TB) transmission—a critical aspect of TB epidemiology—remains understudied and poorly understood. This knowledge gap exists because transmission is a population-level phenotype and effective measurement tools have only recently become available. Whole-genome sequencing of Mtb strains from population-based cohorts has enabled the assessment of transmissibility of different Mtb strains. My research, alongside others, has shown that in various high-burden settings, the majority of ongoing TB transmissions are driven by a small subset of Mtb strains have evolved to be highly transmissible. The identification of highly transmissible strains and their phylogenetically neighboring low-transmissible strains suggests transmissibility of Mtb is an evolving trait, offering a new research opportunity to study the bacterial genetic basis underlying TB transmission. In this proposal, I plan to apply a novel research framework that integrates population genomics and cutting- edge experimental tools to investigate the bacterial genetic basis of high transmissibility. Specifically, (1) I aim to identify key mutations driving high transmissibility in Mtb by leveraging a global collection of 120,000 Mtb genomes from 72 countries. Using population genomics approaches, I seek to identify convergent mutations and common pathways evolved by highly transmissible strains from different countries. (2) I will develop a novel high-throughput bacterial physiological profiling system to characterize the altered bacterial functions in highly transmissible strains under various host-related conditions. (3) Building on my previous findings, I will investigate the role of redox mutations (sseA and trxB2), evolved by highly transmissible strains in Tibet and Peru, in promoting transmission by increasing resistance to reductive stress and facilitating granuloma necrosis. The primary goal is to identify common mechanisms evolved by highly transmissible strains in different countries to enhance transmission. If successful, these insights can guide the development of new preventive strategies tailored to halt the spread of these strains. My cross-disciplinary expertise in population genomics, high-throughput bacterial phenotyping, and classical bacterial genetics uniquely positions me to execute the planned research successfully. Additionally, the approaches developed in this project can be applied to investigate other important bacterial pathogens. This project will also provide a fully genotyped and phenotyped panel of highly transmissible strains as an open resource for other research groups to test new interventions, such as antibiotics and vaccines.