The primary goal of this project is to better understand the biochemical basis for the propensity of group A streptococci to cause human disease and to evaluate the importance of a newly discovered streptococcal inactivator of complement mediated chemotaxis, designated SCFI, to this process. The human complement serum protein C5a, the primary chemotaxin of inflammatory processes, is specifically cleaved by the peptidase activity associated with SCFI. Studies proposed here will further define the specificity of this unique streptococcal peptidase. Isolation and purification procedures will be optimized employing conventional column chromatography, and high pressure chromatographic methods. Experiments with purified enzyme will evaluate the role of this factor in streptococcal virulence; does it influence the resistance of streptococci to phagocytosis, assist colonization of mucosal tissues or retard the inflammatory response? Mice and rabbits will be used for these experiments. Antisera able to neutralize SCFI activity will be tested for the potential to alter virulence of various streptococcal serotypes. The lack of M type specificity makes this protein a potential candidate for a streptococcal vaccine. This possibility will be tested by immunization of animals with purified SCFI. Various animal models of streptococcal infection will be tried. The immunological response to SCFI in humans will be determined by quantitating antibody in sera from healthy and convalescent individuals with an indirect ELISA assay.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020016-06
Application #
3129491
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1983-07-01
Project End
1989-12-31
Budget Start
1988-07-01
Budget End
1989-12-31
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Park, Hae-Sun; Cleary, P Patrick (2005) Active and passive intranasal immunizations with streptococcal surface protein C5a peptidase prevent infection of murine nasal mucosa-associated lymphoid tissue, a functional homologue of human tonsils. Infect Immun 73:7878-86
Brown, C Kent; Gu, Zu-Yi; Matsuka, Yury V et al. (2005) Structure of the streptococcal cell wall C5a peptidase. Proc Natl Acad Sci U S A 102:18391-6
Shet, Anita; Kaplan, Edward L; Johnson, Dwight R et al. (2003) Immune response to group A streptococcal C5a peptidase in children: implications for vaccine development. J Infect Dis 188:809-17
DeMaster, Eric; Schnitzler, Norbert; Cheng, Qi et al. (2002) M(+) group a streptococci are phagocytized and killed in whole blood by C5a-activated polymorphonuclear leukocytes. Infect Immun 70:350-9
Cheng, Qi; Stafslien, Deborah; Purushothaman, Sai Sudha et al. (2002) The group B streptococcal C5a peptidase is both a specific protease and an invasin. Infect Immun 70:2408-13
Cheng, Q; Carlson, B; Pillai, S et al. (2001) Antibody against surface-bound C5a peptidase is opsonic and initiates macrophage killing of group B streptococci. Infect Immun 69:2302-8
Stafslien, D K; Cleary, P P (2000) Characterization of the streptococcal C5a peptidase using a C5a-green fluorescent protein fusion protein substrate. J Bacteriol 182:3254-8
Bormann, N E; Cleary, P P (1997) Transcriptional analysis of mga, a regulatory gene in Streptococcus pyogenes: identification of monocistronic and bicistronic transcripts that phase vary. Gene 200:125-34
Ji, Y; Carlson, B; Kondagunta, A et al. (1997) Intranasal immunization with C5a peptidase prevents nasopharyngeal colonization of mice by the group A Streptococcus. Infect Immun 65:2080-7
Chmouryguina, I; Suvorov, A; Ferrieri, P et al. (1996) Conservation of the C5a peptidase genes in group A and B streptococci. Infect Immun 64:2387-90

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