Cholera is a severe dehydrating disease caused by Vibrio cholerae. Unfortunately, we do not yet know what is the prime functional mediator of protection against cholera. This deficit has impacted development of cholera vaccines, with currently available cholera vaccines providing lower-level and shorter-term protection against cholera, especially in children, than that afforded by previous wild type disease. We and others have generated strong preliminary evidence that protective immunity against cholera is mediated by antibodies at the mucosal surface, and that V. cholerae O-specific polysaccharide (OSP) is the primary antigenic target. V. cholerae is a motile non-invasive enteropathogen with a single polar sheathed flagellum (covered by LPS/OSP). We hypothesize that differences in the follicular T cell immune response between vaccinees and infected cholera patients suppress the immune responses in vaccinees. In addition, we also hypothesize that these differences affect the development, maturation, and functionality of antibody responses against key Vibrio cholerae antigens, O-specific polysaccharide (OSP) and cholera toxin (CT). To address these hypotheses, we propose three specific aims.
Aim #1 : We will use flow cytometry of mononuclear cells isolated from patients with cholera to evaluate follicular T cells (TFH) in relation to infection at different days after onset of disease and following vaccination.
Aim #2 : We will use a novel nano- well approach to isolate single cholera antigen-specific cells by phenotypic characterization in duodenal biopsy specimens (and peripheral blood) of individuals recovering from cholera. We will clone the immunoglobulin chains from these recovered lymphocytes, including plasmablasts, plasma cells, and memory B cells, and we will evaluate cloned antibodies for functionality, as well as affinity maturation and somatic hyper-mutation; we will perform a similar analysis of blood samples of vaccinees.
Aim #3 : We will assess for the presence of V. cholerae agglutinating and anti-motility antibodies in patients with cholera, as well as in vaccinees. This work builds upon a highly-successful and ongoing international collaborative effort between researchers at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh (icddr,b), the Massachusetts General Hospital- Harvard in Boston and Emory University, Atlanta, USA. The goal of this K43 Emerging Global Leader Career Development Program would be to strengthen the skills necessary to become an independent researcher/investigator in mucosal immunology in resource-limited settings.

Public Health Relevance

Vibrio cholerae is the cause of cholera, a significant source of morbidity and mortality, especially in resource-limited areas of the world. In this K43 Emerging Global Leader Career Development Program, Dr. Bhuiyan would use cutting edge immunologic techniques to advance our understanding of T and B cell responses during cholera in Bangladesh.

National Institute of Health (NIH)
Fogarty International Center (FIC)
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International and Cooperative Projects - 1 Study Section (ICP1)
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Sina, Barbara J
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International Center/Diarrhoeal Dis Research
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Islam, Kamrul; Hossain, Motaher; Kelly, Meagan et al. (2018) Anti-O-specific polysaccharide (OSP) immune responses following vaccination with oral cholera vaccine CVD 103-HgR correlate with protection against cholera after infection with wild-type Vibrio cholerae O1 El Tor Inaba in North American volunteers. PLoS Negl Trop Dis 12:e0006376
Bhuiyan, Taufiqur Rahman; Hoq, Mohammad Rubel; Nishat, Naoshin Sharmin et al. (2018) Assessing antigen specific HLA-DR+ antibody secreting cell (DR+ASC) responses in whole blood in enteric infections using an ELISPOT technique. Microbes Infect 20:122-129
Aktar, Amena; Rahman, M Arifur; Afrin, Sadia et al. (2018) Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh. PLoS Negl Trop Dis 12:e0006399
Bourque, Daniel L; Bhuiyan, Taufiqur Rahman; Genereux, Diane P et al. (2018) Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways. Infect Immun 86:
Andrews, Jason R; Khanam, Farhana; Rahman, Nazia et al. (2018) Plasma IgA responses against two Salmonella Typhi antigens identify patients with typhoid fever. Clin Infect Dis :
Domman, Daryl; Chowdhury, Fahima; Khan, Ashraful I et al. (2018) Defining endemic cholera at three levels of spatiotemporal resolution within Bangladesh. Nat Genet 50:951-955
Charles, Richelle C; Nakajima, Rie; Liang, Li et al. (2017) Plasma and Mucosal Immunoglobulin M, Immunoglobulin A, and Immunoglobulin G Responses to the Vibrio cholerae O1 Protein Immunome in Adults With Cholera in Bangladesh. J Infect Dis 216:125-134