The investigators propose using attenuated Salmonella typhimurium in mice as a model for investigation of 6 different avenues designed to enhance immune responses to foreign antigens expressed by bacterial vectors. The proposed approaches include engineering Salmonella to have an """"""""enhanced"""""""" RpoS+ phenotype, specifically decreasing immune response to immunodominant Salmonella antigens in an attempt to """"""""upregulate"""""""" responses against vectored foreign antigens, investigating the influence of attenuating mechanisms on immune responses to heterologous antigens, improve presentation of T-cell epitopes, investigating mechanisms of enhanced antigen delivery via """"""""self-lysing"""""""" bacterial vectors or """"""""runaway"""""""" plasmids which hyperexpress antigen in vivo, and lastly investigate the immunogenicity of DNA delivered by attenuated Salmonellae. The investigators will use heterologous bacterial antigens, and evaluate strains constructed in mice to assess mucosal, humoral and cellular immunity after oral vaccinations. As improved antigen delivery systems are discovered, it is anticipated that they will construct S. typhi or S. paratyphi A derivatives thereof for eventual clinical studies in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE006669-15
Application #
6516378
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Mangan, Dennis F
Project Start
1983-04-01
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
15
Fiscal Year
2002
Total Cost
$327,250
Indirect Cost
Name
Washington University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Curtiss 3rd, Roy; Wanda, Soo-Young; Gunn, Bronwyn M et al. (2009) Salmonella enterica serovar typhimurium strains with regulated delayed attenuation in vivo. Infect Immun 77:1071-82
Bollen, Wendy S; Gunn, Bronwyn M; Mo, Hua et al. (2008) Presence of wild-type and attenuated Salmonella enterica strains in brain tissues following inoculation of mice by different routes. Infect Immun 76:3268-72
Kong, Wei; Wanda, Soo-Young; Zhang, Xin et al. (2008) Regulated programmed lysis of recombinant Salmonella in host tissues to release protective antigens and confer biological containment. Proc Natl Acad Sci U S A 105:9361-6
Konjufca, Vjollca; Jenkins, Mark; Wang, Shifeng et al. (2008) Immunogenicity of recombinant attenuated Salmonella enterica serovar Typhimurium vaccine strains carrying a gene that encodes Eimeria tenella antigen SO7. Infect Immun 76:5745-53
Konjufca, Vjollca; Wanda, Soo-Young; Jenkins, Mark C et al. (2006) A recombinant attenuated Salmonella enterica serovar Typhimurium vaccine encoding Eimeria acervulina antigen offers protection against E. acervulina challenge. Infect Immun 74:6785-96
Uzzau, Sergio; Marogna, Gavino; Leori, Guido Sisinnio et al. (2005) Virulence attenuation and live vaccine potential of aroA, crp cdt cya, and plasmid-cured mutants of Salmonella enterica serovar Abortusovis in mice and sheep. Infect Immun 73:4302-8
Kang, Ho Young; Curtiss 3rd, Roy (2003) Immune responses dependent on antigen location in recombinant attenuated Salmonella typhimurium vaccines following oral immunization. FEMS Immunol Med Microbiol 37:99-104
Kang, Ho Young; Dozois, Charles M; Tinge, Steven A et al. (2002) Transduction-mediated transfer of unmarked deletion and point mutations through use of counterselectable suicide vectors. J Bacteriol 184:307-12
Kang, Ho Young; Srinivasan, Jay; Curtiss 3rd, Roy (2002) Immune responses to recombinant pneumococcal PspA antigen delivered by live attenuated Salmonella enterica serovar typhimurium vaccine. Infect Immun 70:1739-49
Frey, S E; Bollen, W; Sizemore, D et al. (2001) Bacteremia associated with live attenuated chi8110 Salmonella enterica serovar Typhi ISP1820 in healthy adult volunteers. Clin Immunol 101:32-7

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