Humans Surviving Cholera Develop Antibodies against Vibrio cholerae O-Specific Polysaccharide That Inhibit Pathogen Motility

• Type of Material: Article
• Authors: Richelle C. Charles, Massachusetts General Hospital; Meagan Kelly, Massachusetts General Hospital; Jenny M. Tam, Massachusetts General Hospital; Aklima Akter, Massachusetts General Hospital; Motaher Hossain, Massachusetts General Hospital; Kamrul Islam, Massachusetts General Hospital; Rajib Biswas, Massachusetts General Hospital; Mohammad Kamruzzaman, Massachusetts General Hospital; Fahima Chowdhury, International Centre for Diarrhoeal Disease Research; Ashraful I. Khan, International Centre for Diarrhoeal Disease Research; Daniel T. Leung, University of Utah; Ana Weil, Massachusetts General Hospital; Regina C. LaRocque, Massachusetts General Hospital; Taufiqur Rhaman Bhuiyan, International Centre for Diarrhoeal Disease Research; Atiqur Rahman Rahman, International Centre for Diarrhoeal Disease Research; Leslie M. Mayo-Smith, Massachusetts General Hospital; Rachel L. Becker, Massachusetts General Hospital; Jatin M. Vyas, Massachusetts General Hospital; Christina S. Faherty, MassGeneral Hospital for Children; Kourtney P. Nickerson, MassGeneral Hospital for Children; Samantha Giffen, Harvard TH Chan Sch Publ Hlth; Alaina S. Ritter, Massachusetts General Hospital; Matthew K. Waldor, Harvard Medical School; Peng Xu, The National Institute of Diabetes and Digestive and Kidney Diseases; Pavol Kovac, The National Institute of Diabetes and Digestive and Kidney Diseases; Stephen B. Calderwood, Massachusetts General Hospital; Robert C. Kauffman, Emory University; Jens Wrammert, Emory University; Firdausi Qadri, International Centre for Diarrhoeal Disease Research; Jason B. Harris, Massachusetts General Hospital; Edward T. Ryan, Massachusetts General Hospital
• Language: English
• Date: 2020-11-01
• Publisher: AMER SOC MICROBIOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Charles et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/mBio.02847-20
• Title of Journal or Parent Work: MBIO
• Volume: 11
• Issue: 6
• Start Page: 1
• End Page: 13
• Grant/Funding Information: Communicated by This article is a direct contribution from Edward T. Ryan, a Fellow of the American Academy of Microbiology, who arranged for and secured reviews by Nicholas Mantis, Wadsworth Center, New York State Department of Health, and William A. Petri, Jr., University of Virginia, Charlottesville.; This work was supported in part by core grants to the icddr,b and by the Government of the People’s Republic of Bangladesh, Global Affairs Canada (GAC), Swedish International Development Cooperation Agency (SIDA), and the Department of International Development (UKAid). This work was also supported by grants from the National Institutes of Health (R01AI106878 to E.T.R., F.Q., and R.C.C.; U01AI058935 to E.T.R. and R.C.C.; R01AI103055 to J.B.H., J.W., and F.Q.; R01AI137164 to R.C.C. and J.B.H.; R01AI04247 to M.K.W.; R01AI135115 to D.T.L. and F.Q.; R01AI130378 to D.T.L. and T.R.B.; R01AI137127 to J.W.), the Fogarty International Center (FIC) and NIAID training grant in vaccine development and public health (TW005572 to A.A., M.H., K.I., R.B., M. Kamruzzaman, and T.R.B.), an FIC Global Emerging Leader Award (K43TW010362 to T.R.B.), the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program (grant 72424 to R.C.C.), and National Institutes of Allergy and Infectious Diseases (training grant T32 AI007061 to A.S.R. and K22 AI104755 to C.S.F.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
• Keywords: Vibrio cholerae; Science & Technology; cholera; PROTECTION; COLONIZATION; VIRULENCE GENE-EXPRESSION; SURFACE; Microbiology; Life Sciences & Biomedicine; human; LIPOPOLYSACCHARIDE; pathogenesis; MONOCLONAL IGA; motility; ANTILIPOPOLYSACCHARIDE
• Research Categories: Biology, Microbiology; Health Sciences, Public Health

Abstract

The mechanism of protection against cholera afforded by previous illness or vaccination is currently unknown. We have recently shown that antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae correlate highly with protection against cholera. V. cholerae is highly motile and possesses a flagellum sheathed in OSP, and motility of V. cholerae correlates with virulence. Using high-speed video microscopy and building upon previous animal-related work, we demonstrate that sera, polyclonal antibody fractions, and OSP-specific monoclonal antibodies recovered from humans surviving cholera block V. cholerae motility at both subagglutinating and agglutinating concentrations. This antimotility effect is re-versed by preadsorbing sera and polyclonal antibody fractions with purified OSP and is associated with OSP-specific but not flagellin-specific monoclonal antibodies. Fab fragments of OSP-specific polyclonal antibodies do not inhibit motility, suggesting a requirement for antibody-mediated cross-linking in motility inhibition. We show that OSP-specific antibodies do not directly affect V. cholerae viability, but that OSP-specific monoclonal antibody highly protects against death in the murine cholera model. We used in vivo competitive index studies to demonstrate that OSP-specific antibodies impede colonization and survival of V. cholerae in intestinal tissues and that this impact is motility dependent. Our findings suggest that the impedance of motility by antibodies targeting V. cholerae OSP contributes to protection against cholera. IMPORTANCE Cholera is a severe dehydrating illness of humans caused by Vibrio cholerae. V. cholerae is a highly motile bacterium that has a single flagellum covered in lipopolysaccharide (LPS) displaying O-specific polysaccharide (OSP), and V. chol-erae motility correlates with its ability to cause disease. The mechanisms of protection against cholera are not well understood; however, since V. cholerae is a nonin-vasive intestinal pathogen, it is likely that antibodies that bind the pathogen or its products in the intestinal lumen contribute to protection from infection. Here, we demonstrate that OSP-specific antibodies isolated from humans surviving cholera in Bangladesh inhibit V. cholerae motility and are associated with protection against challenge in a motility-dependent manner.