Human enterotoxigenic <i>Escherichia coli</i> (ETEC) infections elicit antibodies that broadly neutralize mucinases of pathogenic <i>Escherichia coli</i> and <i>Shigella</i>
Abstract
Enterotoxigenic Escherichia coli (ETEC) and Shigella are the most common bacterial diarrheal pathogens among young children of low-middle income regions. Enteric pathogens must overcome formidable host defenses, including the protective barrier formed by intestinal mucus. ETEC produce a virulence protein called EatA, a member of the Serine Protease Autotransporter of the Enterobacteriae (SPATE) family, where the secreted passenger domain (EatA p ) specifically degrades MUC2, the major mucus secreted by goblet cells of the human intestine. Notably, some Shigella spp., as well as other diarrheagenic E. coli pathovars, secrete homologues of EatA known as SepA, and Pic. Here, we demonstrate that EatA, SepA, and Pic are functionally redundant MUC2 mucinases and that recombinant monoclonal antibodies (mAbs) derived from plasmablasts of ETEC-infected humans can inhibit MUC2 degradation by all three proteases. We present cryo-EM structures of EatA and the related SPATE proteins, SepA, and Pic, complexed to fragment antigen-binding portions of these mAbs to demonstrate that those targeting a core β-helix epitope shared by all three SPATE molecules broadly neutralize the capacity to degrade MUC2. These mAbs effectively prevent MUC2 degradation by each SPATE as well as mucus penetration by ETEC, Shigella flexneri , and Pic-producing enteroaggregative E. coli (EAEC). We anticipate that these studies could facilitate rational design of vaccines that broadly protect against major enteric pathogens by targeting a shared virulence feature.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
David P. Buckley
Marjahan Akhtar
Mahima Thapa
Department of Pathology and Immunology, Washington University in Saint Louis, School of Medicine
Aaron Schmitz
Department of Pathology and Immunology, Washington University in Saint Louis, School of Medicine
Jackson Turner
Department of Pathology and Immunology, Washington University in Saint Louis, School of Medicine
Tim J. Vickers
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine
Nazia Khatoon
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine
M. Hasanul Kaisar
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine
Jonathan A. Coggin
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine
Debayan Ganguli
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine
Alaullah Sheikh
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine
Renee M. Laird
Military Relevant Bacterial Diseases Department, Naval Medical Research Command
Frédéric Poly
Military Relevant Bacterial Diseases Department, Naval Medical Research Command
Chad K. Porter
Translational and Clinical Research Department, Naval Medical Research Command
Fernando Ruiz-Perez
Department of Pediatrics, University of Virginia School of Medicine
Mark J. Miller
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine
Fahima Chowdhury
Mucosal Immunology and Vaccinology Unit, Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh
Tafiqur R. Bhuiyan
Mucosal Immunology and Vaccinology Unit, Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh
Firdausi Qadri
Sergio Trillo-Muyo
Department of Medical Biochemistry and Cell Biology, University of Gothenburg
Brendan Dolan
Department of Medical Biochemistry and Cell Biology, University of Gothenburg
Sjoerd van der Post
Department of Medical Biochemistry and Cell Biology, University of Gothenburg
Ali Ellebedy
Department of Pathology and Immunology, Washington University in Saint Louis, School of Medicine
Zachary T. Berndsen
Department of Biochemistry, University of Missouri Columbia
James M. Fleckenstein
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine