Our lab studies how bacterial toxins alter host epithelial physiology and the mechanisms by which bacteria benefit from this interaction. We currently use Clostridioides difficile as our model system to study the intricate relationship between pathogens and their hosts.

Clostridiodes difficile is a Gram-positive, spore-forming anaerobe that is the leading cause of antibiotic-associated diarrhea. Disease pathogenesis during C. difficile infection (CDI) is mediated by two large, glucosylating protein toxins, TcdA and TcdB. These toxins enter host cells through receptor-mediated endocytosis. Once inside, the glucosyltransferase payload irreversibly inactivates Rho family GTPases, leading to epithelial damage, inflammation, diarrhea, and in severe cases, pseudomembranous colitis, bowel perforation, and death.

Studying bacterial-host interactions in the intestinal tract is at the core of the lab. We probe these interactions using a suite of in vitro (i.e., purified protein toxins, mammalian cell culture, and human-derived organoids) and in vivo (i.e., mouse models of infection, bacterial genetics, modulation of the microbiome, and antibody interventions) approaches.

Research Overview

Up to 30% of patients who contract C. difficile infection will develop a recurrent CDI within 2-8 weeks of the first episode. Another estimated 25% of patients experience persistent bowel dysfunction for months to years after recovery from CDI. While we have an understanding of how the toxins cause disease, very little is known about what a successful recovery looks like at the tissue and molecular levels.

We are interested in studying the mechanisms of host response and repair after CDI and intoxication with TcdA and TcdB. Specifically by (i) defining lasting impacts of the toxins on different host cell types, (ii) determining how these effects alter host physiological function and protein glycosylation, and (iii) how these changes affect the resident gut microbiota. Our long-term goal is to develop next generation therapeutics to return the gut to homeostasis after infection.

Host Response & Repair

C. difficile uses a combination of Stickland fermentation and central carbon metabolism to replicate and colonize the gut. These metabolic pathways mediate important processes in pathogenesis, including toxin production and sporulation. C. difficile asymptomatically colonizes a subset of the human population, and can persist in mice in its non-toxin-producing vegetative form after recovery from infection.

We are interested in understanding how C. difficile-mediated alterations in host solute transport impacts the metabolic landscape of the gut, and how C. difficile exploits this environment to persist as an asymptomatic colonizer.

Bacterial Physiology

We have an ongoing collaboration with the laboratory of Dr. Angela Kruse to develop and implement new imaging techniques to resolve the host-pathogen interface at an unprecedented level. These techniques include integrating fluorescence, electron, and expansion microscopy, fluorescence in situ hybridization, spatial transcriptomics, and imaging mass spectrometry.