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EXPLORING THE INTERFACE OF CHEMISTRY AND BIOLOGY

Bacteria have evolved remarkable strategies to occupy specific niches and evade detection by the host. In the challenging stomach microenvironment, the gastric bacterium Helicobacter pylori exploits a cancer-associated type IV secretion system nanomachine (cag T4SS) to regulate host immunity and trigger chronic inflammation that drives the development of stomach malignancies. During chronic gastric colonization, the dynamic cag T4SS is deployed to inject a diverse repertoire of immunostimulatory molecular cargo into gastric epithelial cells, including the bacterial oncoprotein CagA, nucleic acids, fragments of peptidoglycan, and lipopolysaccharide (LPS) biosynthesis metabolites. Despite many decades of research, numerous 'black boxes' obscure how this incredible secretion system assembles and transports payload to target cells. One major research objective of the Shaffer Lab is to develop robust chemical tools to accelerate fundamental studies of T4SS biogenesis and function. Our chemical biology approach employs synthetic chemical scaffolds, FDA-approved pharmacophores, biochemical techniques, and reporter cell lines to discover and optimize rationally-designed small molecules that target and disarm these extraordinary nanomachines in diverse bacterial pathogens. Applying structurally and functionally diverse small molecule probes to interrogate mechanisms underlying cag T4SS assembly and cargo translocation will provide candidate chemical scaffolds for innovative early-stage therapeutics that leverage disruption of critical host-pathogen interactions to combat infectious disease.

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ORGANIZATION AND DESIGN OF BACTERIAL MACHINES

How do bacteria engineer and assemble complex nanomachines on the cell surface? We are interested in understanding the ways in which pathogens sense and dock with target cells to trigger the biogenesis of macromolecular complexes to deliver diverse microbial cargo into the host cell. Our laboratory uses genetic and biochemical approaches to understand how the gastric bacterium Helicobacter pylori builds a versatile type IV secretion system (T4SS) used to inject a bacterial oncoprotein, DNA, peptidoglycan, and LPS metabolites into gastric cells. In collaboration with investigators at Caltech, we are using electron cryotomography to dissect the architecture of these elaborate machines in vivo. Together, our studies will uncover how bacteria build the complex T4SS apparatus and orchestrate the transport of molecular substrates across the bacterial envelope. 

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THE BATTLE BETWEEN HOST AND MICROBE

How do bacteria evade host defenses to remain undetected within protected cellular sites? To address this question, we use in vitro infection models, immunoassays, and biochemical techniques to determine how injected bacterial factors hijack cellular pathways to generate a hospitable environment for invading pathogens. Our laboratory seeks to understand how translocated effector molecules interact with danger recognition signaling systems within the host cell. We are particularly interested in defining mechanisms underlying T4SS-mediated pathogenesis induced by the gastric bacterium Helicobacter pylori, and many projects in the Shaffer Lab focus on understanding the host-pathogen interactions that drive microbial stealth.