Tuberculosis (TB) is a leading global public health problem, with high morbidity and mortality in humans, which disproportionately affects marginalized communities worldwide. Until the COVID-19 pandemic, TB was the leading infectious cause of death globally, and in the wake of the pandemic, reduced access to TB diagnosis and treatment have resulted in an increase in TB deaths. Up to a quarter of the world’s population has been infected with Mycobacterium tuberculosis (Mtb), the causal agent of TB. Effective treatment of TB worldwide is further complicated by the emergence of multi-drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB), which are increasing in some regions. Improved understanding of Mtb from both the bacterial and host immune response axes are critical to development of improved diagnostics, therapeutic and vaccine development strategies 

It takes months to treat even drug susceptible Mtb. How are Mtb bacilli so resilient to drug treatment and how does ongoing bacterial evolution affect patient outcomes and our efforts to treat TB? Bacterial genetic variation is an underappreciated driver of variation in tuberculosis disease transmission, progression, and outcomes. Despite this, much of our understanding of Mtb biology is built on a few laboratory strains. To address this discrepancy, we use population genetics and high throughput phenotyping of Mtb isolates to inform bacterial genetics studies. Using these approaches, we’ve linked regulatory networks to drug resistance, identified novel mechanisms of drug tolerance, and linked bacterial variation to disease outcomes. Ongoing work focuses on understanding genetic drivers of currently expanding strains and deep phenotypic characterization of diverse clinical isolates. 

We need new and effective vaccines to control the ongoing TB epidemic. To design these life-saving therapeutics we need a deeper understanding of the immune mechanisms that can kill Mtb and prevent TB disease. We use a diverse array of high-throughput profiling techniques, namely single cell RNA sequencing, biophysical and functional serological profiling, multiplexed flow/mass cytometry and myeloid functional dissection, to understand immune. responses to TB in animal models and human cohorts. These data are then integrated within a systems immunology framework to identify novel protective immune signals in different infection or vaccination contexts. This work includes extensive collaborations through our Hi-IMPAcTB consortium. Our findings have identified avenues of crosstalk between key immunological compartments that associate with both good and bad infection outcomes. 

Our current TB vaccine does not protect adults against pulmonary TB, and we do not have a great way to test the efficacy of new vaccine candidates. We seek to bridge basic science research with translational studies to solve these problems. In collaboration with Eric Rubin at Harvard School of Public Health, Dirk Schnappinger and Sabine Ehrt at Weill Cornell Medical School, and JoAnne Flynn at the University of Pittsburgh, we leverage multiple strategies to (1) convert virulent Mtb strains into safe strains for a vaccine test model, namely TB Human Challenge Model, and (2) improve BCG with higher protection efficacy and safe use.