Our lab is focused on the pathophysiology of Mycobacterium tuberculosis (Mtb) -- the causative agent of tuberculosis (TB). Sadly, TB is still the world's #1 infectious disease killer, only briefly eclipsed by Covid-19. We are a basic biology lab whose research focus spans from questions of fundamental molecular biology to translational applications in novel drug discovery and vaccine design. We believe that studying TB is profoundly enriching and rewarding not only because this is a highly neglected global disease but also because the fundamental biology uncovered is hugely exciting and novel. Our lab works on many different aspects of Mtb biology, such as the ones highlighted below.
Molecular mechanisms of adaptive translation and mistranslation
Although the synthesis of proteins by ribosomes is a universally conserved cellular function, there is increasing evidence that there is a huge amount of regulation and variety in ribosome biology and function that has profound impacts on cellular and organismal phenotypes.
For example, mycobacteria (and indeed the vast majority of bacteria with the notable exception of E. coli) lack the aminoacyl tRNA synthetases for glutamine and asparagine -- and instead use a two-step pathway to generate cognate aminoacylated glutamine and asparagine tRNAs. We showed that despite this "indirect pathway" being both energetically inefficient and highly error-prone, it nonetheless allows Mycobacterium tuberculosis (Mtb) to survive diverse stressful environments such as antibiotic treatment and the host environment -- a phenomenon we term "adaptive mistranslation". We have also recently shown that mycobacteria use different "alternative" ribosome isoforms under nutrient-limiting conditions (that mimic the host environment) that are necessary for survival under these conditions.
We have also discovered several small molecules that target mycobacterial mistranslation that increases susceptibility to antibiotic-mediated killing, the development of drug resistance, and survival within the host. We are actively many questions, many in collaboration with colleagues in structural biology and fundamental biochemistry, that arise from these findings, such as:
1) What are the precise molecular mechanisms that allow ribosomal discrimination of mischarged tRNAs?
2) Can we develop small molecules that target adaptive mistranslation as anti-virulence drugs that also limit the development of de novo antibiotic resistance?
3) How many different types of alternative ribosomes are there, and what are their precise functions and mechanisms of mediating diverse cellular phenotypes?
Molecular mechanisms of tuberculosis antibiotic tolerance
Not all bacteria in a drug-susceptible isogenic population respond the same to antibiotics: some subpopulations are killed more slowly, or not all, and this is termed antibiotic tolerance. Antibiotic tolerance is thought to be the reason that tuberculosis treatment takes at least 6 months, and even then, a significant proportion of patients relapse – without developing drug resistance. Antibiotic tolerance is also considered a "stepping stone" necessary for developing de novo antibiotic resistance. But unlike genetic drug resistance, there are many different forms of antibiotic tolerance that represent entirely distinct bacterial physiological states -- it is not known which of these distinct forms of tolerance are most clinically relevant.
We have previously identified several novel mechanisms mediating tolerance to the first-line anti-TB drug rifampicin, including via mistranslation and via paradoxical upregulation of the drug target in response to rifampicin. We are now leveraging forward genetics to ask:
1) What molecular pathways mediate different forms of antibiotic tolerance and the eventual development of de novo drug resistance?
2) Do different clinical strains of Mtb differ in their propensity for one type of antibiotic tolerance over another?
Antibody-mediated immunity to tuberculosis
Initially dismissed for many decades, there is renewed interest in the role of antibody-mediated immunity to tuberculosis. Our lab leverages a "learning from the body" approach, where we use naturally occurring human immunity to inform mechanistic studies performed in experimental model systems. We have recently demonstrated that a substantial fraction of individuals make antibodies that protect against experimental TB infection, and, in collaboration, we have isolated protective Mtb-specific fully human monoclonal antibodies. We are currently investigating the mechanisms by which antibodies mediate protection against TB to inform both preventative and therapeutic vaccine design by asking these questions:
1) What 'effector' functions mediate antibody-mediated protection?
2) Does the precise TB antigen that antibodies are specific to matter? If so, how can we find which ones are best for subunit vaccine design and therapeutic antibodies?