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Molecular interactions between bacterial and host cells can profoundly impact human health and disease. We study enzymes and other proteins whose biochemical activity dynamically shapes these interactions in the context of gastrointestinal infections. We use a diverse set of chemical and biological tools to address fundamental questions regarding biochemical crosstalk at the host-microbe interface: What enzymes are active during an infection? How does pathogen-associated stress (e.g., from the immune system or antimicrobials) influence protein function in infected cells? What molecular processes do these proteins regulate? By interrogating the functional proteome of bacterial infections, we aim to uncover biochemical pathways that will advance our understanding of gastrointestinal diseases like cholera and stomach cancer and generate new leads for therapeutic targets, activity-based diagnostics, and drug-delivery systems.

Profiling enzymes active in intestinal infections. Cholera is a severe diarrheal disease caused by the intestinal pathogen Vibrio cholerae. Using a technique called activity-based proteomics, we recently identified several pathogen- and host-secreted enzymes active in an animal model of cholera and in human disease. We are using genetic and biochemical methods to characterize the in vivo substrates of these enzymes and the molecular processes that promote enzyme secretion and activation in the gut. We are also applying similar tools to identify enzymes that mediate host-microbe interactions in other gastrointestinal infections.

Chemically dissecting the redox biology of Helicobacter pylori infection. Helicobacter pylori is a stomach bacterium found in half of the global population that can cause gastric cancer. The molecular processes that promote H. pylori-induced carcinogenesis are still poorly understood, but oxidative stress is considered an important factor. We are using chemical probes to identify redox-signaling pathways triggered by oxidative stress in H. pylori-infected cells and animals that may contribute to carcinogenesis.