Bacterial Pathogenesis

Type IV pili are fimbrial appendages found on the surfaces of many bacteria and are important for adhesion, colonization, biofilm formation and horizontal gene transfer. They consist of 1000s of copies of one or a few pilin proteins arranged in a superhelical formation that can be actively extended and retracted from the bacterial surface. Type IV pili have been extensively studied in Gram-negative bacteria. We have recently solved the first high-resolution structures of Type IV pilin proteins from a Gram-positive bacterium, Clostridium difficile. We are pursuing structures of the additional C. difficile Type IV pilin proteins, determining the supramolecular architecture of the multi-component pilus, and identifying host cell receptors that they engage. We are also investigating another gut microbe, Helicobacter pylori, which is the major causative agent of gastric cancer. H. pylori injects an oncoprotein, CagA, through a Type IV Secretion System into gastric epithelial cells where it carries out numerous biological functions, including the dysregulation of kinase-dependent signal transduction cascades and the apoptotic program, to ultimately cause cellular transformation. We are studying how CagA is delivered through the Type IV Secretion System, how other Cag proteins allow the secretion system to specifically engage host cells and the molecular mechanisms by which CagA dysregulates normal host cell functions.

Selected recent publications:

Daniel A. Bonsor, Qing Zhao, Barbara Schmidinger, Evelyn Weiss, Jingheng Wang, Daniel Deredge, Robert Beadenkopf, Blaine Dow, Wolfgang Fischer, Dorothy Beckett, Patrick L. Wintrode, Rainer Haas and Eric J. Sundberg* (2018). The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA. The EMBO Journal(2018) 37: e98664 | PDF | Article Link

Sandra Postel, Daniel Deredge, Daniel A. Bonsor, Xiong Yu, Kay Diederichs, Saskia Helmsing, Aviv Vromen, Assaf Friedler, Michael Hust, Edward H. Egelman, Dorothy Beckett, Patrick L. Wintrode and Eric J. Sundberg*. Bacterial flagellar capping proteins adopt diverse oligomeric states. eLife, pii: e18857. doi: 10.7554/eLife.18857 | PDF | Article Link

Kurt H. Piepenbrink, Grace A. Maldarelli, Claudia F. Martinez de la Peña, George L. Mulvey, Glen D. Armstrong, Michael S. Donnenberg, and Eric J. Sundberg* (2015). Structural and evolutionary analyses show unique stabilization strategies in the Type IV pili of Clostridium difficile. Structure, 23(2), 385-396.