Causes and Consequences of Pathogen Heterogeneity in Tuberculosis
For a bacterial infection to linger after antibiotic treatment only a small handful of bacteria need to remain. What is different about these cells from the ones that were easily killed? We think the answer to this question will help to develop therapies that treat bacterial infections more rapidly and more completely.
This is especially important for tuberculosis. Despite having antibiotics to treat TB, global mortality rates are not rapidly decreasing, and TB continues to kill nearly 2 million people each year. Patients with drug-susceptible TB (the vast majority) must undergo 6—9 months of antibiotic therapy with a combination of 4 drugs. Any shorter antibiotic regimen allows subpopulations of bacteria to survive and cause relapse.
My lab tries to understand TB from the perspective of single cells. We are measuring important traits of single pathogen cells (permeability to drugs, metabolic activity, and others), and correlating the variability we find to pathogen and host cell survival. To do this, we leverage technologies from seemingly disparate fields. These include imaging methods like super-resolution microscopy and advanced bacterial genetic tools like parallel transposon sequencing. Discovering the drivers of variability and defining the nature of tolerant subpopulations could lead to novel interventions designed to shorten treatment. Such therapeutics would greatly help reduce the global burden of TB disease.