PARASITE INDUCED CATABOLISM IN MAMMALS

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Parasitic and bacterial invasion of mammals is associated with a number of common metabolic derangements of the host. One of these is the induction of a catabolic state which, when prolonged, can lead to cachexia, shock and death. We have recently isolated a macrophage product, cachectin, which is made in response to T. brucei, P. berghei, and endotoxin that inhibits the synthesis of the enzyme lipoprotein lipase of adipocytes in vivo and 3T3-L1 pre-adipocytes in vitro. Subsequent analysis of the effect of the cachectin on the 3T3-L1 cells has revealed that cachectin also inhibits the synthesis of other key anabolic enzymes essential for fatty acid synthesis-acetyl Co-A carboxylase and fatty acid synthetase. The inhibition of these anabolic enzymes is highly selective, since plus labeling of the cells with S35-methionine reveals that the general pattern of incorporation of radioactivity into protein is the same with or without the mediator. Cachetin appears to be part of a communication system between the immune system and other cells of the body involved in energy storage and utilization. In the current application it is proposed to examine 1) what role cachectin might have in the cachectic state commonly observed in animals infected with parasites, 2) possible biological effects of cachectin on other cell types and 3) the cloning of cachectin by recombinant DNA technology. These studies offer the possibility of elucidating a type of pathogenic modality common in a wide variety of parasitic diseases, which may lead to the development of convergent therapeutic approaches.