This is a proposal for a K08 Mentored Clinical Scientist Research Career Development Award training program. The candidate, Dr. Richelle C. Charles, recently completed an Infectious Disease clinical fellowship in the combined training program between Massachusetts General Hospital and the Brigham and Women's Hospital, Boston. She is now in a period of extended research training in the Division of Infectious Diseases at the Massachusetts General Hospital, and plans to pursue a career as an independent biomedical investigator focused on mucosal and enteric infections of import in resource-limited areas of the world. This application proposes a five-year K08 training program under the primary mentorship of Dr. Edward T. Ryan in the Division of Infectious Disease of the Massachusetts General Hospital. Dr. Stephen B. Calderwood, within the same division, will provide co-mentorship throughout the course of the proposed program. The program involves both didactic and practical training focused on high-throughput immuno-proteomic approaches, and builds upon ongoing collaborations with the International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B), Harvard Institute of Proteomics, and Arizona State University. The major project focus will be the application of immuno-proteomics to the study of protective immunity in human cholera infection, an infection that remains endemic in over 50 countries. An estimated 3-5 million individuals develop cholera each year, resulting in approximately 100,000 deaths. Although cholera vaccines do induce a protective immune response, immunity is short-lived, lasting approximately 6-24 months. In comparison, natural infection with cholera results in protective immunity that lasts years or decades;however, the mediators of the protective immune response to cholera are poorly understood. In this application, the trainee will use a high-throughput protein-based platform, the Nucleic Acid Programmable Protein Array, to (1) characterize serum anti-V. cholerae immune responses in cholera patients and vaccinees, and correlate baseline serum humoral anti-V. cholerae immunity with protection from disease in household contacts of cholera patients;(2) characterize mucosal anti-V. cholerae immune response, using the antibody-in lymphocyte (ALS ) assay, a marker of mucosal immunity, and (3) characterize anti-V. cholerae memory B cell responses during human wild-type V. cholerae infection, and correlate anti-V. cholerae memory B cell immunity with protection from disease in household contacts of cholera patients. Antigens identified by high throughput screening will then be examined in more detail, including in immunologic confirmatory studies. The results of these studies could provide important insights into protective immunity of human cholera infection, and could lead to improved vaccination strategies against cholera. A K08 award would provide the candidate with critical skills and experience in scientific investigation, and facilitate her development into an independent physician scientist. Project Narrative: Vibrio cholerae is the cause of cholera, causes significant morbidity and mortality, and predominantly affects impoverished individuals in resource-limited areas of the world. Although current vaccines have been shown to be safe and immunogenic, none have been shown to provide the durable immunity conferred by natural infection. Characterization of the protective immune response of wild-type cholera infection would aid in the development of improved cholera vaccination approaches.

Public Health Relevance

Vibrio cholerae is the cause of cholera, causes significant morbidity and mortality, and predominantly affects impoverished individuals in resource-limited areas of the world. Although current vaccines have been shown to be safe and immunogenic, none have been shown to provide the durable immunity conferred by natural infection. Characterization of the protective immune response of wild-type cholera infection would aid in the development of improved cholera vaccination approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI089721-03
Application #
8259838
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Cassels, Frederick J
Project Start
2010-06-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$137,160
Indirect Cost
$10,160
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Uddin, Taher; Aktar, Amena; Xu, Peng et al. (2014) Immune responses to O-specific polysaccharide and lipopolysaccharide of Vibrio cholerae O1 Ogawa in adult Bangladeshi recipients of an oral killed cholera vaccine and comparison to responses in patients with cholera. Am J Trop Med Hyg 90:873-81
Weil, Ana A; Begum, Yasmin; Chowdhury, Fahima et al. (2014) Bacterial shedding in household contacts of cholera patients in Dhaka, Bangladesh. Am J Trop Med Hyg 91:738-42
Leung, Daniel T; Bhuiyan, Taufiqur R; Nishat, Naoshin S et al. (2014) Circulating mucosal associated invariant T cells are activated in Vibrio cholerae O1 infection and associated with lipopolysaccharide antibody responses. PLoS Negl Trop Dis 8:e3076
Alam, Mohammad Murshid; Bufano, Megan Kelly; Xu, Peng et al. (2014) Evaluation in mice of a conjugate vaccine for cholera made from Vibrio cholerae O1 (Ogawa) O-specific polysaccharide. PLoS Negl Trop Dis 8:e2683
Bhuiyan, Saruar; Sayeed, Abu; Khanam, Farhana et al. (2014) Cellular and cytokine responses to Salmonella enterica serotype Typhi proteins in patients with typhoid fever in Bangladesh. Am J Trop Med Hyg 90:1024-30
Gunn, John S; Marshall, Joanna M; Baker, Stephen et al. (2014) Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence. Trends Microbiol 22:648-55
Charles, Richelle C; Liang, Li; Khanam, Farhana et al. (2014) Immunoproteomic analysis of antibody in lymphocyte supernatant in patients with typhoid fever in Bangladesh. Clin Vaccine Immunol 21:280-5
Seed, Kimberley D; Yen, Minmin; Shapiro, B Jesse et al. (2014) Evolutionary consequences of intra-patient phage predation on microbial populations. Elife 3:e03497
Charles, Richelle C; Hilaire, Isabelle J; Mayo-Smith, Leslie M et al. (2014) Immunogenicity of a killed bivalent (O1 and O139) whole cell oral cholera vaccine, Shanchol, in Haiti. PLoS Negl Trop Dis 8:e2828
Charles, Richelle C; Sultana, Tania; Alam, Mohammad Murshid et al. (2013) Identification of immunogenic Salmonella enterica serotype Typhi antigens expressed in chronic biliary carriers of S. Typhi in Kathmandu, Nepal. PLoS Negl Trop Dis 7:e2335

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