Trypanosoma brucei metabolism is under circadian control

Abstract

TX 75390-9111, USAThe Earth's rotation forced life to evolve under cyclic day and night environmental changes. In order to anticipate such daily cycles, prokaryote and eukaryote free-living organisms evolved intrinsic clocks that regulate physiological and behavioral processes. Daily rhythms have been observed in organisms living within hosts, such as parasites. Whether parasites have intrinsic molecular clocks or whether they simply respond to host rhythmic physiological cues remains unknown. Here we show that Trypanosoma brucei, the causative agent of human sleeping sickness, has an intrinsic circadian clock that regulates its metabolism in two different stages of the life cycle. We found that in vitro approximately 10% of genes in T. brucei are expressed with a circadian rhythm. The maximum expression of these genes occurs at two different phases of the day and may depend on a posttranscriptional mechanism. Circadian genes are enriched in cellular metabolic pathways, and coincide with two peaks of intracellular ATP concentration. Moreover, daily changes in the parasite population lead to differences in suramin sensitivity, a drug commonly used to treat Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature

Circadian rhythms in parasites

“…Although no daily oscillation in parasite number has been detected in T . brucei -infected animals [25], we have recently shown that in culture, these extracellular parasites have intrinsic circadian rhythms in gene expression [27]. Such rhythms were identified by initially entraining the parasite population with temperature cycles followed by assessing the transcriptome by RNA-seq of samples every 4 hours for 2 days.…”

“…brucei , transcription is believed to be constitutive and gene expression regulated mostly at the posttranscriptional level [38, 39]. The circadian clock in this parasite appears to also be driven mainly by posttranscriptional mechanisms because polycistronic units (PCUs) are not synchronous and individual transcripts within a PCU can be noncyclic or cyclic with different phases of transcript levels [27]. …”

“…We showed that T . brucei parasites (both mammalian-bloodstream and insect-procyclic forms) are able to entrain to temperature cycles differing by only 5°C, whereas the bloodstream forms do not appear to entrain to light/dark cycles [27]. It is possible, however, that—similar to peripheral clocks—other stimuli can also entrain these and other parasites, such as nutrient availability [49], hormones [50, 51], and perhaps even rhythmic immune pressure [52].…”

“…brucei also has a circadian clock—it’s able to generate circadian rhythmic gene expression in the absence of host cells and in the absence of any stimuli [27]. What is this rhythm for?…”

Disruption of the coordination between host circadian rhythms and malaria parasite development alters the duration of the intraerythrocytic cycle

“…Many parasite species exhibit daily rhythms in behaviour and/or development that are scheduled to optimally exploit periodicities in transmission opportunities and/or resource availability 8,9 . The parasitic protozoan Trypanosoma brucei, for example, possesses an intrinsic circadian clock that drives metabolic rhythms 10 . Malaria parasites complete their intra-erythrocytic developmental cycle (IDC) in 24h (or multiples of 24 h depending on the parasite species), suggesting a circadian basis to the asexual cell cycle 11 .…”