scholarly journals Timing of host feeding drives rhythms in parasite replication

2017 ◽  
Author(s):  
Kimberley F. Prior ◽  
Daan R. van der Veen ◽  
Aidan J. O’Donnell ◽  
Katherine Cumnock ◽  
David Schneider ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Time Of Day ◽  
Circadian Oscillator ◽  
Parasite Development ◽  
Feeding Time ◽  
Host Immune System ◽  
Host Feeding ◽  
Malaria Parasites ◽  
Feeding Rhythms ◽  
The Brain

AbstractCircadian rhythms enable organisms to synchronise the processes underpinning survival and reproduction to anticipate daily changes in the external environment. Recent work shows that daily (circadian) rhythms also enable parasites to maximise fitness in the context of ecological interactions with their hosts. Because parasite rhythms matter for their fitness, understanding how they are regulated could lead to innovative ways to reduce the severity and spread of diseases. Here, we examine how host circadian rhythms influence rhythms in the asexual replication of malaria parasites. Asexual replication is responsible for the severity of malaria and fuels transmission of the disease, yet, how parasite rhythms are driven remains a mystery. We perturbed feeding rhythms of hosts by 12 hours (i.e. diurnal feeding in nocturnal mice) to desynchronise the host’s peripheral oscillators from the central, light-entrained oscillator in the brain and their rhythmic outputs. We demonstrate that the rhythms of rodent malaria parasites in day-fed hosts become inverted relative to the rhythms of parasites in night-fed hosts. Our results reveal that the host’s peripheral rhythms (associated with the timing of feeding and metabolism), but not rhythms driven by the central, light-entrained circadian oscillator in the brain, determine the timing (phase) of parasite rhythms. Further investigation reveals that parasite rhythms correlate closely with blood glucose rhythms. In addition, we show that parasite rhythms resynchronise to the altered host feeding rhythms when food availability is shifted, which is not mediated through rhythms in the host immune system. Our observations suggest that parasites actively control their developmental rhythms. Finally, counter to expectation, the severity of disease symptoms expressed by hosts was not affected by desynchronisation of their central and peripheral rhythms. Our study at the intersection of disease ecology and chronobiology opens up a new arena for studying host-parasite-vector coevolution and has broad implications for applied bioscience.Author summaryHow cycles of asexual replication by malaria parasites are coordinated to occur in synchrony with the circadian rhythms of the host is a long-standing mystery. We reveal that rhythms associated with the time-of-day that hosts feed are responsible for the timing of rhythms in parasite development. Specifically, we altered host feeding time to phase-shift peripheral rhythms, whilst leaving rhythms driven by the central circadian oscillator in the brain unchanged. We found that parasite developmental rhythms remained synchronous but changed their phase, by 12 hours, to follow the timing of host feeding. Furthermore, our results suggest that parasites themselves schedule rhythms in their replication to coordinate with rhythms in glucose in the host’s blood, rather than have rhythms imposed upon them by, for example, host immune responses. Our findings reveal a novel relationship between hosts and parasites that if disrupted, could reduce both the severity and transmission of malaria infection.

scholarly journals An essential amino acid synchronises malaria parasite development with daily host rhythms

2020 ◽  
Author(s):  
Kimberley F. Prior ◽  
Benita Middleton ◽  
Alíz T.Y. Owolabi ◽  
Mary L. Westwood ◽  
Jacob Holland ◽  
...  
Keyword(s):  
Amino Acid ◽  
Large Scale ◽  
Blood Stage ◽  
Parasite Development ◽  
Host Feeding ◽  
Malaria Parasites ◽  
Disease Symptoms ◽  
Development Cycle ◽  
Feeding Rhythms ◽  
Blood Stage Malaria

SummaryThe replication of blood-stage malaria parasites is synchronised to the host’s daily feeding rhythm. We demonstrate that a metabolite provided to the parasite from the host’s food can set the schedule for Plasmodium chabaudi’s intraerythrocytic development cycle (IDC). First, a large-scale screen reveals multiple rhythmic metabolites in the blood that match the timing of the IDC, but only one - the amino acid isoleucine - that malaria parasites must scavenge from host food. Second, perturbing the timing of isoleucine provision and withdrawal demonstrate that parasites use isoleucine to schedule and synchronise their replication. Thus, periodicity in the concentration of isoleucine in the blood, driven by host-feeding rhythms, explains why timing is beneficial to the parasite and how it coordinates with host rhythms. Blood-stage replication of malaria parasites is responsible for the severity of disease symptoms and fuels transmission; disrupting metabolite-sensing by parasites offers a novel intervention to reduce parasite fitness.

scholarly journals Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

2020 ◽  
Vol 287 (1932) ◽  
pp. 20200347
Author(s):  
Aidan J. O'Donnell ◽  
Kimberley F. Prior ◽  
Sarah E. Reece
Keyword(s):  
Time Of Day ◽  
Circadian Clocks ◽  
Host Feeding ◽  
Malaria Parasites ◽  
Disease Symptoms ◽  
Transmission Investment ◽  
Clock Proteins ◽  
Clock Mutant ◽  
Feeding Rhythms ◽  
Parasite Replication

Circadian clocks coordinate organisms' activities with daily cycles in their environment. Parasites are subject to daily rhythms in the within-host environment, resulting from clock-control of host activities, including immune responses. Parasites also exhibit rhythms in their activities: the timing of within-host replication by malaria parasites is coordinated to host feeding rhythms. Precisely which host feeding-related rhythm(s) parasites align with and how this is achieved are unknown. Understanding rhythmic replication in malaria parasites matters because it underpins disease symptoms and fuels transmission investment. We test if rhythmicity in parasite replication is coordinated with the host's feeding-related rhythms and/or rhythms driven by the host's canonical circadian clock. We find that parasite rhythms coordinate with the time of day that hosts feed in both wild-type and clock-mutant hosts, whereas parasite rhythms become dampened in clock-mutant hosts that eat continuously. Our results hold whether infections are initiated with synchronous or with desynchronized parasites. We conclude that malaria parasite replication is coordinated to rhythmic host processes that are independent of the core-clock proteins PERIOD 1 and 2; most likely, a periodic nutrient made available when the host digests food. Thus, novel interventions could disrupt parasite rhythms to reduce their fitness, without interference by host clock-controlled homeostasis.

scholarly journals Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

2019 ◽  
Author(s):  
Aidan J. O’Donnell ◽  
Kimberley F. Prior ◽  
Sarah E. Reece
Keyword(s):  
Immune Responses ◽  
Time Of Day ◽  
Circadian Clocks ◽  
Mutant Mice ◽  
Host Feeding ◽  
Wild Type ◽  
Malaria Parasites ◽  
Disease Symptoms ◽  
Clock Mutant ◽  
Daily Cycles

SUMMARYCircadian clocks coordinate organisms’ activities with daily cycles in their environment. Parasites are subject to daily rhythms in the within-host environment, resulting from clock-control of host behaviours and physiologies, including immune responses. Parasites also exhibit rhythms in within-host activities; the timing of host feeding sets the timing of the within-host replication of malaria parasites. Why host feeding matters to parasites and how coordination with feeding is achieved are unknown. Determining whether parasites coordinate with clock-driven food-related rhythms of their hosts matters because rhythmic replication underpins disease symptoms and fuels transmission.We find that parasite rhythms became coordinated with the time of day that hosts feed in both wild type and clock-mutant mice, whereas parasite rhythmicity was lost in clock-mutant mice that fed continuously. These patterns occurred regardless of whether infections were initiated with synchronous or with desynchronised parasites.Malaria parasite rhythms are not driven by canonical clock-controlled host rhythms. Instead, we propose parasites coordinate with a temporally-restricted nutrient that becomes available through host digestion or are influenced by a separate clock-independent host process that directly responds to feeding. Thus, interventions could disrupt parasite rhythms to reduce their fitness, without interference by host clock-controlled-homeostasis.

scholarly journals Ecology of asynchronous asexual replication: the intraerythrocytic development cycle of Plasmodium berghei is resistant to host rhythms

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Aidan J. O’Donnell ◽  
Sarah E. Reece
Keyword(s):  
Plasmodium Berghei ◽  
Time Of Day ◽  
Host Feeding ◽  
Ecological Interactions ◽  
Daily Rhythms ◽  
Development Cycle ◽  
Weak Evidence ◽  
Feeding Rhythms ◽  
Taxonomic Range ◽  
Malaria Species

Abstract Background Daily periodicity in the diverse activities of parasites occurs across a broad taxonomic range. The rhythms exhibited by parasites are thought to be adaptations that allow parasites to cope with, or exploit, the consequences of host activities that follow daily rhythms. Malaria parasites (Plasmodium) are well-known for their synchronized cycles of replication within host red blood cells. Whilst most species of Plasmodium appear sensitive to the timing of the daily rhythms of hosts, and even vectors, some species present no detectable rhythms in blood-stage replication. Why the intraerythrocytic development cycle (IDC) of, for example Plasmodium chabaudi, is governed by host rhythms, yet seems completely independent of host rhythms in Plasmodium berghei, another rodent malaria species, is mysterious. Methods This study reports a series of five experiments probing the relationships between the asynchronous IDC schedule of P. berghei and the rhythms of hosts and vectors by manipulating host time-of-day, photoperiod and feeding rhythms. Results The results reveal that: (i) a lack coordination between host and parasite rhythms does not impose appreciable fitness costs on P. berghei; (ii) the IDC schedule of P. berghei is impervious to host rhythms, including altered photoperiod and host-feeding-related rhythms; (iii) there is weak evidence for daily rhythms in the density and activities of transmission stages; but (iv), these rhythms have little consequence for successful transmission to mosquitoes. Conclusions Overall, host rhythms do not affect the performance of P. berghei and its asynchronous IDC is resistant to the scheduling forces that underpin synchronous replication in closely related parasites. This suggests that natural variation in the IDC schedule across species represents different parasite strategies that maximize fitness. Thus, subtle differences in the ecological interactions between parasites and their hosts/vectors may select for the evolution of very different IDC schedules.

scholarly journals Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid

2021 ◽  
Vol 6 ◽  
pp. 186
Author(s):  
Kimberley F. Prior ◽  
Benita Middleton ◽  
Alíz T.Y. Owolabi ◽  
Mary L. Westwood ◽  
Jacob Holland ◽  
...  
Keyword(s):  
Amino Acid ◽  
Large Scale ◽  
Time Of Day ◽  
Asexual Development ◽  
Host Feeding ◽  
Malaria Parasites ◽  
Disease Symptoms ◽  
Daily Rhythmicity

Background: Rapid asexual replication of blood stage malaria parasites is responsible for the severity of disease symptoms and fuels the production of transmission forms. Here, we demonstrate that the Plasmodium chabaudi’s schedule for asexual replication can be orchestrated by isoleucine, a metabolite provided to the parasite in periodic manner due to the host’s rhythmic intake of food. Methods: We infect female C57BL/6 and Per1/2-null TTFL clock-disrupted mice with 1×105 red blood cells containing P. chabaudi (DK genotype). We perturb the timing of rhythms in asexual replication and host feeding-fasting cycles to identify nutrients with rhythms that match all combinations of host and parasite rhythms. We then test whether perturbing the availability of the best candidate nutrient in vitro elicits changes their schedule for asexual development. Results: Our large-scale metabolomics experiment and follow up experiments reveal that only one metabolite - the amino acid isoleucine – fits criteria for a time-of-day cue used by parasites to set the schedule for replication. The response to isoleucine is a parasite strategy rather than solely the consequences of a constraint imposed by host rhythms, because unlike when parasites are deprived of other essential nutrients, they suffer no apparent costs from isoleucine withdrawal. Conclusions: Overall, our data suggest parasites can use the daily rhythmicity of blood-isoleucine concentration to synchronise asexual development with the availability of isoleucine, and potentially other resources, that arrive in the blood in a periodic manner due to the host’s daily feeding-fasting cycle. Identifying both how and why parasites keep time opens avenues for interventions; interfering with the parasite’s time-keeping mechanism may stall replication, increasing the efficacy of drugs and immune responses, and could also prevent parasites from entering dormancy to tolerate drugs.

scholarly journals Synchrony between daily rhythms of malaria parasites and hosts is driven by an essential amino acid

2021 ◽  
Vol 6 ◽  
pp. 186
Author(s):  
Kimberley F. Prior ◽  
Benita Middleton ◽  
Alíz T.Y. Owolabi ◽  
Mary L. Westwood ◽  
Jacob Holland ◽  
...  
Keyword(s):  
Amino Acid ◽  
Large Scale ◽  
Time Of Day ◽  
Asexual Development ◽  
Host Feeding ◽  
Malaria Parasites ◽  
Disease Symptoms ◽  
Daily Rhythmicity

Background: Rapid asexual replication of blood stage malaria parasites is responsible for the severity of disease symptoms and fuels the production of transmission forms. Here, we demonstrate that a Plasmodium chabaudi’s schedule for asexual replication can be orchestrated by isoleucine, a metabolite provided to the parasite in a periodic manner due to the host’s rhythmic intake of food. Methods: We infect female C57BL/6 and Per1/2-null mice which have a disrupted canonical (transcription translation feedback loop, TTFL) clock with 1×105 red blood cells containing P. chabaudi (DK genotype). We perturb the timing of rhythms in asexual replication and host feeding-fasting cycles to identify nutrients with rhythms that match all combinations of host and parasite rhythms. We then test whether perturbing the availability of the best candidate nutrient in vitro changes the schedule for asexual development. Results: Our large-scale metabolomics experiment and follow up experiments reveal that only one metabolite - the amino acid isoleucine – fits criteria for a time-of-day cue used by parasites to set the schedule for replication. The response to isoleucine is a parasite strategy rather than solely the consequences of a constraint imposed by host rhythms, because unlike when parasites are deprived of other essential nutrients, they suffer no apparent costs from isoleucine withdrawal. Conclusions: Overall, our data suggest parasites can use the daily rhythmicity of blood-isoleucine concentration to synchronise asexual development with the availability of isoleucine, and potentially other resources, that arrive in the blood in a periodic manner due to the host’s daily feeding-fasting cycle. Identifying both how and why parasites keep time opens avenues for interventions; interfering with the parasite’s time-keeping mechanism may stall replication, increasing the efficacy of drugs and immune responses, and could also prevent parasites from entering dormancy to tolerate drugs.

296 Sex differences in sleep and wakefulness of police officers working shifts: evidence from a field study

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A118-A118
Author(s):  
Gabriela Caetano ◽  
Laura Kervezee ◽  
Fernando Gonzales-Aste ◽  
Philippe Boudreau ◽  
Diane Boivin
Keyword(s):  
Sex Differences ◽  
Circadian Rhythms ◽  
Shift Work ◽  
Police Officers ◽  
Field Studies ◽  
Time Of Day ◽  
Cycle Phase ◽  
Shift Workers ◽  
Work Related ◽  
Time Awake

Abstract Introduction National reports of work-related injuries found the excess risk of work injury attributed to shift work to be significantly higher among women. The Working Time Society (WTS) concluded that male sex is one of the few factors that is “consistently associated with perceived or actual shift work tolerance”. However, it is unclear if physiological parameters are involved. Laboratory-controlled studies report sex differences in circadian rhythms (body temperature, melatonin). In sleep deprivation protocols, alertness and cognitive performances were affected by sex, menstrual cycle phase and hormonal contraceptives [HC] use. Nevertheless, field studies that compare male and female shift workers are scarce. Methods An observational study including 76 police officers working on patrol: 56 males and 20 females (11 using [HC], 6 not using [non-HC] and 3 with unknown use of hormonal contraception) aged 32.0 ± 5.3 years. Participants were followed throughout a month-long work cycle (1,457 morning, evening, night, or other shifts, plus rest days). They filled out time-stamped questionnaires (Samn-Perelli, KSS, Visual Analogue Scales, ~5/day; sleep and work-related information, ~1–2/day), completed 5-min Psychomotor Vigilance Tasks (PVT, ~2/day), and wore an actigraph to collect activity data. Linear mixed-effects models were used to analyze the effects of group, time awake and time-of-day on fatigue, sleepiness, alertness, mood and PVT measures. Results Self-reported measures and psychomotor performance significantly varied with time awake and time-of-day. Fatigue and sleepiness levels were significantly higher among female compared to male police officers, both with time awake and across the 24-h day. These variations were similar between non-HC females and the other groups. Compared to males, HC females were more fatigued and less alert, both with time awake and across the 24-h day, and sleepier with time awake. Having children at home did not explain these differences. Conclusion The results of this study expand our knowledge on the sex differences in the sleep and circadian physiology and demonstrate a critical effect of HC on women fatigue, sleepiness and alertness when working shifts. Sex and hormonal parameters must be considered in occupational medicine as well as in future laboratory and field studies on shift workers and circadian rhythms. Support (if any) IRSST, FRQS.

scholarly journals Understanding Quantitative Circadian Regulations Are Crucial Towards Advancing Chronotherapy

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 883 ◽  
Author(s):  
Debajyoti Chowdhury ◽  
Chao Wang ◽  
Ai-Ping Lu ◽  
Hai-Long Zhu
Keyword(s):  
Circadian Rhythms ◽  
Molecular Mechanisms ◽  
Temporal Stability ◽  
Biological Rhythms ◽  
Integrative Approach ◽  
Peripheral Tissues ◽  
Innovative Strategies ◽  
Neural Connections ◽  
Core Components ◽  
The Brain

Circadian rhythms have a deep impact on most aspects of physiology. In most organisms, especially mammals, the biological rhythms are maintained by the indigenous circadian clockwork around geophysical time (~24-h). These rhythms originate inside cells. Several core components are interconnected through transcriptional/translational feedback loops to generate molecular oscillations. They are tightly controlled over time. Also, they exert temporal controls over many fundamental physiological activities. This helps in coordinating the body’s internal time with the external environments. The mammalian circadian clockwork is composed of a hierarchy of oscillators, which play roles at molecular, cellular, and higher levels. The master oscillation has been found to be developed at the hypothalamic suprachiasmatic nucleus in the brain. It acts as the core pacemaker and drives the transmission of the oscillation signals. These signals are distributed across different peripheral tissues through humoral and neural connections. The synchronization among the master oscillator and tissue-specific oscillators offer overall temporal stability to mammals. Recent technological advancements help us to study the circadian rhythms at dynamic scale and systems level. Here, we outline the current understanding of circadian clockwork in terms of molecular mechanisms and interdisciplinary concepts. We have also focused on the importance of the integrative approach to decode several crucial intricacies. This review indicates the emergence of such a comprehensive approach. It will essentially accelerate the circadian research with more innovative strategies, such as developing evidence-based chronotherapeutics to restore de-synchronized circadian rhythms.

scholarly journals Daily rhythms of both host and parasite affect antimalarial drug efficacy

2021 ◽  
Author(s):  
Alíz T Y Owolabi ◽  
Sarah E Reece ◽  
Petra Schneider
Keyword(s):  
Drug Treatment ◽  
Developmental Stage ◽  
Antimalarial Drug ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Time Of Day ◽  
Parasite Development ◽  
Daily Rhythms ◽  
Parasite Plasmodium

Abstract Background and objectives Circadian rhythms contribute to treatment efficacy in several non-communicable diseases. However, chronotherapy (administering drugs at a particular time-of-day) against infectious diseases has been overlooked. Yet, the daily rhythms of both hosts and disease-causing agents can impact the efficacy of drug treatment. We use the rodent malaria parasite Plasmodium chabaudi, to test if the daily rhythms of hosts, parasites, and their interactions, affect sensitivity to the key antimalarial, artemisinin. Methodology Asexual malaria parasites develop rhythmically in the host’s blood, in a manner timed to coordinate with host daily rhythms. Our experiments coupled or decoupled the timing of parasite and host rhythms, and we administered artemisinin at different times of day to coincide with when parasites were either at an early (ring) or later (trophozoite) developmental stage. We quantified the impacts of parasite developmental stage, and alignment of parasite and host rhythms, on drug sensitivity. Results We find that rings were less sensitive to artemisinin than trophozoites, and this difference was exacerbated when parasite and host rhythms were misaligned, with little direct contribution of host time-of-day on its own. Furthermore, the blood concentration of haem at the point of treatment correlated positively with artemisinin efficacy but only when parasite and host rhythms were aligned. Conclusions and implications Parasite rhythms influence drug sensitivity in vivo. The hitherto unknown modulation by alignment between parasite and host daily rhythms suggests that disrupting the timing of parasite development could be a novel chronotherapeutic approach. Lay Summary We reveal that chronotherapy (providing medicines at a particular time-of-day) could improve treatment for malaria infections. Specifically, parasites’ developmental stage at the time of treatment and the coordination of timing between parasite and host both affect how well antimalarial drug treatment works.

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