Group A streptococcal pyrogenic exotoxin: pyrogenicity, alteration of blood-brain barrier, and separation of sites for pyrogenicity and enhancement of lethal endotoxin shock.

Group A streptococcal pyrogenic exotoxin type C (SPE C) was shown to produce fever by crossing the blood-brain barrier. The toxin directly stimulated the hypothalamic fever response control center, thus bypassing a requirement for endogenous pyrogen release. SPE C was detected in the cerebrospinal fluids of toxin-treated rabbits by pyrogen tests and a hemagglutination inhibition assay. The toxin altered the permeability of the blood-brain barrier to endotoxin, Streptococcus pneumoniae, and Haemophilus influenzae as well as to itself. SPE C did not alter the in vivo differential and total counts of peripheral blood leukocytes and did not elicit endogenous pyrogen release from leukocytes in vitro. In vivo, peripheral blood platelet counts remained unchanged after SPE treatment. Cycloheximide pretreatment of rabbits did not inhibit fever production by SP C. In contrast to the hypothermia observed in mice treated with endotoxin intravenously susceptibility to lethal endotoxin shock. The abilities of SPE C to produce fever and enhance lethal shock were shown to be separate functions of the molecule; fever results from stimulation of the hypothalamus, and enhancement appears not to involve the central nervous system.