Cardiotoxicity of Streptococcal Pyrogenic Exotoxin

Schlievert, Patrick

Abstract

The research studies the mechanism(s) by which group A streptococcal pyrogenic exotoxins (SPES) predispose the host to myocardial damage and lethal shock by other agents, perhaps the most important property of these toxins. Attempts will be made to identify sites (epitopes) on the toxins which bind antibodies, including neutralizing, immune system cells and heart cells, in attempts to identify regions necessary for biological toxicity. The SPEs have the capacity to cause scarlet fever, a toxic-shock syndrome-like illness, and may contribute to the early events in development of rheumatic fever, other autoimmune diseases, and vascular diseases later in life. Research to elucidate the mechanism of enhanced susceptibility to myocardial damage and shock will proceed in several directions. SPE types A and C, as representative exotoxins, will be tested for capacity to bind specifically to heart and liver cells, and splenocytes. Isolated heart and liver cells will then be investigated as the most likely targets for enhancement. Exotoxins alone, in combination, and together with endotoxin (a representative second agent) will be tested for capacity to disrupt cell membrane integrity, alter macromolecular synthesis, induce interleukin 1, and alter endotoxin uptake and subsequent detoxification. Studies to identify sites for target cell interaction and antibody binding will proceed in three directions. Monoclonal antibodies against SPEs A and C will be used to block biological activities. Proteolytic enzymes, other cleavage agents, and genetic techniques will be used to generate toxin fragments with partial biological activities, capacities to bind cells and antibodies.