Group A streptococcus (GAS) is a common cause of bacterial pharyngitis and impetigo. Severe sequelae associated with these infections include fatal sepsis, rheumatic fever and acute poststreptococcal glomerulonephritis. Virulence is associated with a complex fibrillar layer of surface proteins, including immunoglobulin Fc receptors, M protein and a C5a peptidase (SCPA). An important first line of defense to many bacterial pathogens is accumulated PMNS at the site of infection. Attraction is mediated by chemotactic stimuli such as Interleukin 8 and the complement protein C5a. Our discovery of SCPA advanced a new concept in bacterial pathogenesis. SCPA is bound to the cell surface, posed to inactivate C5a at the surface where it is formed. We postulate that SCPA impedes initial clearance of streptococci by inhibiting the influx of PMN. This provides time for biosynthetic adjustment and permits them to increase their numbers. Furthermore, neutralization of SCPA activity by antibody could disarm invading bacteria and promote their rapid clearance. We will continue to the explore the universality of C5a targeted peptidases among mucosal bacterial pathogens. The highest priority is to test the impact of SCPA on the capacity of streptococci to colonize the nasopharynx and skin in animal models. Molecular and biochemical methods will further define substrate specificity. Understanding the importance of C5a peptidases in microbial virulence will expand our knowledge of host-parasite interactions and perhaps open new avenues for streptococcal vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020016-11
Application #
2061083
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1989-12-01
Project End
1996-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
11
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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