STREPTOCOCCAL INACTIVATOR IN HUMAN CHEMOATTRACTANTS

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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 SCP, to this process. The human complement serum protein C5a, the primary chemotaxin of inflammatory processes, is specifically cleaved by the peptidase activity associated with SCP. Studies proposed here will further define the specificity of this unique streptococcal peptidase. A biochemical peptidase assay employing synthetic peptides will be developed and used to define determinants of substrate specificity. The cloned SCP gene will be sequenced and the deduced amino acid sequence compared to that of other streptococcal proteins, and other peptidases, in order to identify functional domains. Experiments with purified enzyme will evaluate the role of this factor in streptococcal virulence; does it assist colonization of mucosal tissues? An intranasal mouse model will be used for these experiments. Antibody, IgG and sIgA, able to neutralize SCP activity will be tested for the potential to alter virulence of various streptococcal serotypes. The lack of M vaccine. This possibility will be tested by immunization of mice using a genetically engineered, attenuated salmonella strain carrying the SCP gene. The secretory immunological response to SCP in humans will be defined by quantitating antibody in saliva from healthy and convalescent children, and adults by ELISA.