Environmental Sensing of Fatty Acids in African Trypanosomes

Trypanosoma brucei is a eukaryotic parasite that causes African sleeping sickness. It is transmitted by the tsetse fly. Throughout its life cycle, the parasite must adapt to the dramatically different environments presented by its mammalian and insect hosts. T. brucei possesses two ways to satisfy its demand for one key nutrient, fatty acids: fatty acid synthesis (FAS) and uptake of fatty acids and lipids from the environment. Several observations suggest that the parasite can regulate both the acyl‐chain specificity and the overall activity of its FAS pathways in order to meet its needs. As an example of chain‐length regulation, the bloodstream form (BSF) parasites have a huge demand for myristate (C14:0), which is needed for the dimyristoyl GPI anchor of its surface glycoprotein coat. Thus, BSF preferentially synthesize myristate both in vitro and in vivo . However, if BSF are starved for fatty acids by growth in low lipid media, in vivo labeling experiments reveal that BSF will readily elongate [3H]myristate. As an example of overall FAS regulation, T. brucei can adapt to growth in low‐lipid media. When grown in media containing 20% of lipids present in normal media, the parasite growth rate is inhibited by 90%. After 2 days, however, the parasite growth rate recovers and approaches the control levels by 3–4 days. To start to understand the molecular mechanisms underlying these observations, we are using a forward genetics approach to identify gene products involved in fatty acid sensing and adaptive FAS regulation. We are employing a T. brucei RNA interference library and using two different screening methods: 1) loss of adaptation to low lipid media; and 2) loss of sensitivity to toxic levels of an exogenous fatty acid.