Abstract
The African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its life cycle. 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 were rapidly killed as glucose concentrations fell, while short stumpy bloodstream form parasites persisted to differentiate into the insect-stage procyclic form parasite. The rate of differentiation was lower 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 nonmetabolizable glucose analogs, and these parasites were found to have upregulated amino acid metabolic pathway component gene expression. 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 also an important signaling molecule.IMPORTANCE As the African trypanosome Trypanosoma brucei completes its life cycle, 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 life cycle 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 nondividing short stumpy parasite remains viable and undergoes differentiation to the next life cycle 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.
Highlights
The African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its life cycle
One major change is the rapid (ϳ15-min) depletion of environmental glucose, the primary carbon source used to generate ATP during bloodstream infection [11]. This reduction in available glucose is at least in part due to the metabolic activity of the parasites in the blood meal. Both pleomorphic long slender (LS) and short stumpy (SS) parasites isolated from infected rodents rapidly consume glucose in vitro with 0.5 mM glucose being nearly depleted from culture medium after a single day by both life cycle stages (Fig. 1A)
After 1 day, glucose levels were reduced to 37 Ϯ 0.70 and 62 Ϯ 0.60 M for LS and SS, respectively, and the hexose concentration continued to fall on day two, reaching 1.7 Ϯ 0.70 and 15 Ϯ 0.90 M
Summary
The African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its life cycle. IMPORTANCE As the African trypanosome Trypanosoma brucei completes its life cycle, it encounters many different environments Adaptation to these environments includes modulation of metabolic pathways to parallel the availability of nutrients. Such is the case for the vector-borne African trypanosome, Trypanosoma brucei, a kinetoplastid parasite that is the causative agent of African sleeping sickness This parasite, which is transmitted by tsetse flies, undergoes a series of developmental steps that yield life cycle stages which are uniquely adapted for life in the distinct hosts. In T. brucei development, differentiation events occur in both the mammalian host and insect vector As their density increases in the vertebrate bloodstream, long slender (LS) blood form parasites perceive a quorum-dependent parasite-derived signal that triggers differentiation into short stumpy (SS) blood form parasites, a nondividing form arrested in G0 of the cell cycle [1]. When these SS parasites, which are preadapted for life in the tsetse fly vector [2], are engulfed by a tsetse fly during a blood meal, they quickly differentiate into dividing procyclic form (PF) parasites that are competent for completion of the life cycle in the fly
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