Microbial pathogenes which infect mucosal surfaces of the body continue to cause significant human morbidity and mortality. Current parenteral vaccination strategies for these infections are frequently ineffective. Antigens in the lumen of the gastrointestinal tract bind to specialized M cells in the epithelium and are presented to underlying cells of the immune system, leading to proliferation and differentiation of IgA- committed, antigen-specific lymphocytes which circulate to the lamina propria of diverse mucosal surfaces. This dissemination of a mucosal immune response from an individual inductive site to diverse effector sites has been termed the common mucosal immune system. Vibrio cholerae is an excellent model for studying mucosal immunity and stimulation of a common mucosal immune response. V. cholerae selectively adheres to M cells of the gastrointestinal tract and natural infection with V. cholerae is followed by long-lasting, systemic and mucosal immune responses. V. cholerae also has many advantages as a vector system for delivering antigens from heterologous organisms to the mucosal immune system. The long-term goal of these studies is to develop V. cholerae as a live, oral, attenuated vaccine vector strain for delivery of heterologous antigens to the mucosal immune system. There are four SPECIFIC AIMS in the present proposal: (1) optimizing in vivo expression of heterologous antigens by live, oral, attenuated vector strains of V. cholerae, using the B subunit of cholera toxin (CTxB) as a model antigen; (2) analysis of a fusion protein between the serine rich protein of Entamoeba histolytica (SREHP) and CtxB, expressed by a live, oral, attenuated V. cholerae vector, for inducing anti-SREHP mucosal immunity in an animal model; (3) examining the role of mutant LT-I as an immunoadjuvant, when expressed by live, oral, attenuated V. cholerae vector strains; and (4) use of live, oral, attenuated V. cholerae vector strains to deliver epitopes of toxin A of Clostridium difficile: application of general principles to a specific mucosal infection and assessment of the role of antigenic context in the mucosal immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040725-04
Application #
6124385
Study Section
Special Emphasis Panel (ZRG5-BM-2 (01))
Program Officer
Hamilton, Frank A
Project Start
1996-12-01
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
4
Fiscal Year
2000
Total Cost
$295,478
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Rychert, Jenna; Creely, David; Mayo-Smith, Leslie M et al. (2015) Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of Vibrio cholerae. J Clin Microbiol 53:329-31
Khan, Ashraful I; Chowdhury, Fahima; Harris, Jason B et al. (2010) Comparison of clinical features and immunological parameters of patients with dehydrating diarrhoea infected with Inaba or Ogawa serotypes of Vibrio cholerae O1. Scand J Infect Dis 42:48-56
Harris, Jason B; Podolsky, Michael J; Bhuiyan, Taufiqur R et al. (2009) Immunologic responses to Vibrio cholerae in patients co-infected with intestinal parasites in Bangladesh. PLoS Negl Trop Dis 3:e403
Rollenhagen, Julianne E; Kalsy, Anuj; Saksena, Rina et al. (2009) Transcutaneous immunization with a synthetic hexasaccharide-protein conjugate induces anti-Vibrio cholerae lipopolysaccharide responses in mice. Vaccine 27:4917-22
Harris, Jason B; LaRocque, Regina C; Chowdhury, Fahima et al. (2008) Susceptibility to Vibrio cholerae infection in a cohort of household contacts of patients with cholera in Bangladesh. PLoS Negl Trop Dis 2:e221
Chowdhury, Fahima; Khan, Ashraful I; Harris, Jason B et al. (2008) A comparison of clinical and immunologic features in children and older patients hospitalized with severe cholera in Bangladesh. Pediatr Infect Dis J 27:986-92
Harris, Aaron M; Chowdhury, Fahima; Begum, Yasmin Ara et al. (2008) Shifting prevalence of major diarrheal pathogens in patients seeking hospital care during floods in 1998, 2004, and 2007 in Dhaka, Bangladesh. Am J Trop Med Hyg 79:708-14
Jayasekera, Channa R; Harris, Jason B; Bhuiyan, Saruar et al. (2008) Cholera toxin-specific memory B cell responses are induced in patients with dehydrating diarrhea caused by Vibrio cholerae O1. J Infect Dis 198:1055-61
LaRocque, Regina C; Krastins, Bryan; Harris, Jason B et al. (2008) Proteomic analysis of Vibrio cholerae in human stool. Infect Immun 76:4145-51
Ghose, Chandrabali; Kalsy, Anuj; Sheikh, Alaullah et al. (2007) Transcutaneous immunization with Clostridium difficile toxoid A induces systemic and mucosal immune responses and toxin A-neutralizing antibodies in mice. Infect Immun 75:2826-32

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