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We found that the cholera-induced responses were characterized by high levels of somatic hypermutation and large clonal expansions. A majority of the expansions targeted cholera toxin (CT) or lipopolysaccharide (LPS). Using a novel proteomics approach, we were able to identify sialidase as another major antigen targeted by the antibody response to<jats:named-content content-type=\"genus-species\">Vibrio cholerae<\/jats:named-content>infection. Antitoxin MAbs targeted both the A and B subunits, and most were also potent neutralizers of enterotoxigenic<jats:named-content content-type=\"genus-species\">Escherichia coli<\/jats:named-content>heat-labile toxin. LPS-specific MAbs uniformly targeted the O-specific polysaccharide, with no detectable responses to either the core or the lipid moiety of LPS. Interestingly, the LPS-specific antibodies varied widely in serotype specificity and functional characteristics. One participant infected with the Ogawa serotype produced highly mutated LPS-specific antibodies that preferentially bound the previously circulating Inaba serotype. This demonstrates durable memory against a polysaccharide antigen presented at the mucosal surface and provides a mechanism for the long-term, partial heterotypic immunity seen following cholera.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Cholera is a diarrheal disease that results in significant mortality. While oral cholera vaccines are beneficial, they do not achieve equivalent protection compared to infection with<jats:named-content content-type=\"genus-species\">Vibrio cholerae<\/jats:named-content>. Although antibodies likely mediate protection, the mechanisms of immunity following cholera are poorly understood, and a detailed understanding of antibody responses to cholera is of significance for human health. In this study, we characterized the human response to cholera at the single-plasmablast, monoclonal antibody level. Although this approach has not been widely applied to the study of human bacterial infection, we were able to uncover the basis of cross-reactivity between different<jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>serotypes and the likely impact of prior enterotoxigenic<jats:named-content content-type=\"genus-species\">Escherichia coli<\/jats:named-content>exposure on the response to cholera, as well as identify novel antigenic targets. In addition to improving our understanding of the repertoire and function of the antibody response to cholera in humans, this study has implications for future cholera vaccination efforts.<\/jats:p>","DOI":"10.1128\/mbio.02021-16","type":"journal-article","created":{"date-parts":[[2016,12,23]],"date-time":"2016-12-23T18:48:16Z","timestamp":1482518896000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":68,"title":["Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells"],"prefix":"10.1128","volume":"7","author":[{"given":"Robert C.","family":"Kauffman","sequence":"first","affiliation":[{"name":"Division of Infectious Disease, Department of Pediatrics, Emory University, School of Medicine, Atlanta, Georgia, USA"},{"name":"Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, 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