Abstract
ABSTRACTWe characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts. 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 Vibrio cholerae infection. Antitoxin MAbs targeted both the A and B subunits, and most were also potent neutralizers of enterotoxigenic Escherichia coli 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.
Highlights
We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts
We measured plasmablast responses in 11 adult men and women with severe cholera who presented at the International Centre for Diarrhoeal Disease Research, Bangladesh, hospital in Dhaka, Bangladesh, between 2011 and 2013. (Patient details are summarized in Table S1 in the supplemental material.) All patients were infected with the V. cholerae O1 Ogawa serotype, which accounted for 99.5% of cholera cases in Dhaka during the study period
Compared to healthy individuals without cholera from either an area where cholera is endemic (Dhaka, Bangladesh) or an area where it is nonendemic (United States), cholera induced a significant plasmablast expansion, representing up to 29% of the total B cells at day 7 following cholera (Fig. 1A)
Summary
We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts. 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. Evaluation of the B cell response to cholera at a monoclonal level permits analyses that cannot be addressed by studying polyclonal responses This allows for an analysis of the origin of cross-reactivity between different V. cholerae serotypes, defining the repertoire breadth of responding B cells, and an assessment of the functional properties of the individual antibodies targeting V. cholerae. These studies may be instructive for future vaccine efforts against cholera, enterotoxigenic Escherichia coli (ETEC), and other mucosal infections
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