Activated eosinophils (EOS) destroy parasites but can also damage host tissue. Although the most common human disease caused by EOS is allergies, the most catastrophic is eosinophilic endocarditis, the second leading cause of cardiac deaths in tropical Africa and Asia. We have unexpectedly found that the dietarily derived pseudohalide thiocyanate (SCN), not Br as previously thought, is the primary substrate for the unique eosinophil peroxidase (EPO) in physiologic fluids. This is a provocative results because the product of this reaction, HOSCN, is a far weaker oxidant than are the potent by nonspecific bleaching oxidants HOBr and HOCl, the main product of neutrophil myeloperoxidase. We hypothesize that precisely because of its restricted oxidant reactivity, HOSCN, unlike membrane lytic HOBr and HOCI, penetrates intact membranes to oxidize specific intracellular protein sulfhydryl (SHs). This SH- specificity may endow HOSCN with the capacity to kill parasites preferentially over host cells. However, in conditions of serum SCN- depletion, EPO will instead oxidize Br to produce indiscriminantly toxic HOBr, which severely damages adjacent host tissues. Thus, SCN-may both mediated and modulate EO cytotoxicity. Our first specific aim is to show that EOs physiologically activated by large opsonized particles produce HOSCN. Our second specific aim is to define molecular mechanisms underlying the direct toxicity of reagent HOSCN for EOs themselves, for mammalian cells, and for schistosomules, a classical model of parasite infestation. We hypothesize that HOSCN is a SH-specific metabolic poison, and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is its principal target. Our third specific aim is to characterize possible indirect mechanisms of HOSCN toxicity involving secondary oxidative interactions with H2O2 other cationic eosinophil granule proteins, proteases, and anti-proteases. Toxic as HOSCN may be for host tissue, however, HOBr is at least tenfold more lethal. Therefore our fourth specific aim is to characterize the halide composition of serum from individuals with hypereosinophilia heart disease. We hypothesize that such patients peroxidatively deplete their own serum of SCN-, low levels of which are a risk factor for host tissue damage by permitting EPO to oxidize Br to HOBr instead of SCN to HOSCN. Our fifth specific aim is to establish a mouse model of eosinophilic endocarditis utilizing transgenic mice that overexpress the eosinophil- specific growth factor interleukin 5 (IL-5). We will examine the role of SCN in regulating cardiac damage in this model by experimentally augmenting of depleting serum SCN. These studies, if successful, will define an important, hitherto unsuspected role for SCN- in governing the toxicity of EOs for parasites and host tissues. If so, we will have identified a simple therapeutic strategy for blunting host toxicity -- dietary supplementation of SCN -- that could be applied even in a Third World.