Glucose signaling is important for nutrient adaptation during differentiation of pleomorphic African trypanosomes

Abstract

The African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its lifecycle. During transition from mammalian blood to insect vector gut, parasites experience a rapid reduction in environmental glucose. Here we describe how pleomorphic parasites respond to glucose depletion with a focus on parasite changes in energy metabolism and growth. Long slender bloodstream form parasites are rapidly killed as glucose concentrations fall, while the short stumpy bloodstream form parasites persist to differentiate into the insect stage procyclic form parasite. The rate of differentiation was slower than that triggered by other cues but reached physiological rates when combined with cold shock. Both differentiation and growth of resulting procyclic form parasites were inhibited by glucose and its non-metabolizable analogs in a concentration dependent manner. Procyclic form parasites differentiated from short stumpy form parasites in glucose depleted medium significantly upregulated gene expression of amino acid metabolic pathway components when compared to procyclic forms generated by cis-aconitate treatment. Additionally, growth of these parasite was inhibited by the presence of either glucose or 6-deoxyglucose. In summary, glucose transitions from the primary metabolite of the blood stage infection to a negative regulator of cell development and growth in the insect vector, suggesting that the hexose is not only a key metabolic agent but is also an important signaling molecule.\n\nAuthor SummaryAs the African trypanosome, Trypanosoma brucei, completes its lifecycle, it encounters many different environments. Adaptation to these environments includes modulation of metabolic pathways to parallel the availability of nutrients. Here, we describe how the blood-dwelling lifecycle stages of the African trypanosome, which consume glucose to meet their nutritional needs, respond differently to culture in the near absence of glucose. The proliferative long slender parasites rapidly die, while the non-dividing short stumpy remains viable and undergoes differentiation to the next lifecycle stage, the procyclic form parasite. Interestingly a sugar analog that cannot be used as an energy source inhibited the process. Furthermore, the growth of procyclic form parasite that resulted from the event was inhibited by glucose, a behavior that is similar to that of parasites isolated from tsetse flies. Our findings suggest that glucose sensing serves as an important modulator of nutrient adaptation in the parasite.