Human enterotoxigenic Escherichia coli (ETEC) infections elicit antibodies that broadly neutralize mucinases of pathogenic Escherichia coli and Shigella

• 成果类型: Article
• 署名作者: Buckley, David P.; Akhtar, Marjahan; Thapa, Mahima; Schmitz, Aaron; Turner, Jackson; Vickers, Tim J.; Khatoon, Nazia; Kaisar, M. Hasanul; Coggin, Jonathan A.; Ganguli, Debayan; Sheikh, Alaullah; Laird, Renee M.; Poly, Frederic; Porter, Chad K.; Ruiz-Perez, Fernando; Miller, Mark J.; Chowdhury, Fahima; Bhuiyan, Tafiqur R.; Qadri, Firdausi; Trillo-Muyo, Sergio; Dolan, Brendan; van der Post, Sjoerd; Ellebedy, Ali; Berndsen, Zachary T.; Fleckenstein, James M.
• 署名单位: University of Missouri System; University of Missouri Columbia; Washington University (WUSTL); Washington University (WUSTL); University of Virginia (UVA) Health System; University of Virginia; University of Gothenburg; Washington University (WUSTL); Washington University (WUSTL); Vanderbilt University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2614012123
• 发表日期: 2026-06-23
• 页码: e2614012123
• 关键词: vaccines; enterotoxigenic E. coli; Shigella; serine protease; mucin; SERINE-PROTEASE AUTOTRANSPORTERS; global enteric multicenter; middle-income countries; MUC2 MUCIN; crystal-structure; PASSENGER DOMAIN; CHILDREN; flexneri; secretion; etiology

摘要

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 (EatAp) 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 beta-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.