Interactions between the streptococcal inhibitor of complement (sic) protein and its targets in neutrophils

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The neutrophil is the first and most abundant leukocyte to be delivered to a site of inflammation or infection. Neutrophils are equipped with an antimicrobial arsenal that destroys invading pathogens. However, many pathogens have devised strategies to avoid killing by neutrophils. Streptococcus pyogenes (S. pyogenes) or group A Streptococcus (GAS), a gram-positive bacterium, is one of them. S. pyogenes can cause a variety of human diseases, including pharyngitis (strep throat), cellulites, impetigo, and the potentially fatal necrotizing fascitis (flesh eating disease) and streptococcal toxic shock syndrome. My long-term objective is to understand how S. pyogenes evades killing by neutrophils. My general hypothesis is that exotoxins secreted by S. pyogenes interact with protein components of the neutrophil defense machineries to prevent killing of the microorganism. My specific hypothesis is that a novel protein named sic (streptococcal inhibitor of complement), which is secreted by S. pyogenes, targets specific proteins in neutrophils which regulate its ability to ingest microorganisms (phagocytosis) or secrete microbicidal enzymes. Our specific objectives are to (i) identify and characterize the specific targets of sic in neutrophils and (ii) to analyze the molecular interactions between sic and its protein targets, and examine the molecular effect of sic on secretion and phagocytosis. We will use a combination of modern methodologies in cellular and molecular biology, immunology and biochemistry to pursue our goals, including mass spectrometry, yeast-two hybrid analysis, protein expression and purification, two-dimensional gel electrophoresis, and immunoelectron and confocal microscopy. These investigations will allow us to elucidate the functional significance of the molecular interactions between sic and its protein targets in neutrophils. Thus, our studies will advance our knowledge of S. pyogenes mechanisms that evolved to prevent its destruction by neutrophils.