The disease schistosomiasis is fundamentally due to the immunological reaction of the host to the presence of the parasite's eggs imbedded within its liver. This fact makes viable the concept of eliminating the disease by targeting drugs to destroy the egg producing capability of the female schistosome. This concept has been partially confirmed by previous research but we feel that real progress in this area awaits a clearer understanding of the biochemical mechanisms responsible for egg production. To this end, we have been studying the role which lipids play in regulating egg production with a particular interest in the dolichols, a class of lipids which play a significant role in the glycosylation of proteins. Since the production of these lipids is regulated by the rate-limiting enzyme HMG-CoA reductase, we explored the biochemical and physiological effect of a selective and potent inhibitor of this enzyme called mevinolin. We observed that when mevinolin was given at high doses to infected mice it reduced the appearance of the liver pathology normally induced by the parasite while at lower doses this change was not observed. In fact, worms retrieved from the latter were found to produce 6 times more eggs when placed in culture and compared to worms recovered from nonmevinolintreated mice. When mevinolin is incubated in the presence of cultured parasites it appears to selectively block egg production by the parasite. This drug also inhibits the conversion of 14C-acetate into an isoprenoidlike compound that is necessary for the glycosylation of parasite proteins. Our results are consistent with the idea that the female schistosome's HMGCoA reductase activity is elevated when exposed to mevinolin in vivo and that the activity of this enzyme regulates the production of a nonsterol lipid which in turn regulates the rate at which the female produces eggs. Our immediate goal is to confirm the above hypothesis and then attempt to identify agents that can stop egg production and thus reduce or eliminate the pathology associated with schistosomiasis.
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