The purpose of the proposed investigations is to study the role of monocytes and monocyte products in the pathogenesis of infections caused by Staphylococcus aureus. Many aspects of staphylococcal pathogenesis, particularly the systemic toxicity and shock often seen in nonbacteremic infections, may be the consequence of endogenous mediators produced by monocytes in response to infection. Tumor necrosis factor (TNF)/ cachectin and interleukin-1 (IL-1)/endogenous pyrogen are monocyte products to which have been attributed many features of shock induced by gram-negative endotoxin. Very little is know, however, about the role of these mediators in disease induced by S. aureus. These studies will investigate the roles of TNF and IL- 1 in the mediation of staphylococcal pathogenesis, using models developed in vitro and in vivo. TNF and IL-1 of rabbit origin will be purified and studied in an established rabbit model of staphylococcal infection. Antibodies directed against these proteins will be developed, and the effect of these antibodies on disease induced by TNF, IL-1, and specific staphylococcal toxins will be studied. In addition, the role of arachidonic acid metabolites in mediating the effects of TNF and Il-1 will be studied in vivo by the administration of inhibitors of arachidonic acid metabolism. The induction by staphylococcal products of monokine production will also be studied in vitro. The response of monocytes to stimulation will be studied using assays specific for TNF, IL-1 and products of arachidonic acid metabolism. The relationship between these monocyte products, as well as factors regulating their production, will be studied. The synergy between staphylococcal toxins and gram-negative endotoxin on monocyte stimulation, which has been invoked s a mechanism by which these toxins may cause disease, will be investigated. Finally, collaborative experiments with other investigators designed to elucidate the structural determinants of pathogenicity of staphylococcal toxins will be continued.
