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 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 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.

scholarly journals Effects of age on circadian rhythms are similar in wild-type and heterozygous Clock mutant mice

2004 ◽  
Vol 25 (4) ◽  
pp. 517-523 ◽  
Author(s):  
Daniel E. Kolker ◽  
Martha Hotz Vitaterna ◽  
Ethan M. Fruechte ◽  
Joseph S. Takahashi ◽  
Fred W. Turek
Keyword(s):  
Circadian Rhythms ◽  
Mutant Mice ◽  
Wild Type ◽  
Clock Mutant

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.

Clockmutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol and/or cholic acid diet

2008 ◽  
Vol 294 (1) ◽  
pp. E120-E130 ◽  
Author(s):  
Takashi Kudo ◽  
Mihoko Kawashima ◽  
Toru Tamagawa ◽  
Shigenobu Shibata
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Cholic Acid ◽  
Mouse Liver ◽  
Clock Genes ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mutant Mice ◽  
Wild Type ◽  
Clock Mutant

Cholesterol (CH) homeostasis in the liver is regulated by enzymes of CH synthesis such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and catabolic enzymes such as cytochrome P-450, family 7, subfamily A, and polypeptide 1 (CYP7A1). Since a circadian clock controls the gene expression of these enzymes, these genes exhibit circadian rhythm in the liver. In this study, we examined the relationship between a diet containing CH and/or cholic acid (CA) and the circadian regulation of Hmgcr, low-density lipoprotein receptor ( Ldlr), and Cyp7a1 gene expression in the mouse liver. A 4-wk CA diet lowered and eventually abolished the circadian expression of these genes. Not only clock genes such as period homolog 2 (Drosophila) ( Per2) and brain and muscle arnt-like protein-1 ( Bmal1) but also clock-controlled genes such as Hmgcr, Ldlr, and Cyp7a1 showed a reduced and arrhythmic expression pattern in the liver of Clock mutant mice. The reduced gene expression of Cyp7a1 in mice fed a diet containing CA or CH + CA was remarkable in the liver of Clock mutants compared with wild-type mice, and high liver CH accumulation was apparent in Clock mutant mice. In contrast, a CH diet without CA only elevated Cyp7a1 expression in both wild-type and Clock mutant mice. The present findings indicate that normal circadian clock function is important for the regulation of CH homeostasis in the mouse liver, especially in conjunction with a diet containing high CH and CA.

scholarly journals Diurnal Amplitudes of Arterial Pressure and Heart Rate Are Dampened in Clock Mutant Mice and Adrenalectomized Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3576-3580 ◽  
Author(s):  
Hiroyoshi Sei ◽  
Katsutaka Oishi ◽  
Sachiko Chikahisa ◽  
Kazuyoshi Kitaoka ◽  
Eiji Takeda ◽  
...  
Keyword(s):  
Heart Rate ◽  
Arterial Pressure ◽  
Clock Gene ◽  
Clock Genes ◽  
Plasma Aldosterone ◽  
Mutant Mice ◽  
Wild Type ◽  
Clock Mutant ◽  
Wild Type Control

Arterial pressure (AP), heart rate (HR), and cardiovascular diseases, including ischemic heart attack and cerebrovascular accident, show diurnal variation. Evidence that circadian-related genes contribute to cardiovascular control has been accumulated. In this study, we measured the AP and HR of Clock mutant mice on the Jcl/ICR background to determine the role of the Clock gene in cardiovascular function. Mice with mutated Clock genes had a dampened diurnal rhythm of AP and HR, compared with wild-type control mice, and this difference disappeared after adrenalectomy. The diurnal acrophase in both mean arterial pressure and HR was delayed significantly in Clock mutant mice, compared with wild-type mice, and this difference remained after adrenalectomy. Clock mutant mice had a lower concentration of plasma aldosterone, compared with wild-type mice. Our data suggest that the adrenal gland is involved in the diurnal amplitude, but not the acrophase, of AP and HR, and that the function of the Clock gene may be related to the nondipping type of AP elevation.

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 Tomato wall-associated kinase SlWak1 acts in an Fls2- and Fls3-dependent manner to promote apoplastic immune responses to Pseudomonas syringae

2020 ◽  
Author(s):  
Ning Zhang ◽  
Marina A Pombo ◽  
Hernan G Rosli ◽  
Gregory B Martin
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Pseudomonas Syringae ◽  
Molecular Mechanisms ◽  
Plant Immunity ◽  
Transcript Abundance ◽  
Dependent Manner ◽  
Wild Type ◽  
Disease Symptoms

Wall-associated kinases (Waks) are known to be important components of plant immunity against various pathogens including Pseudomonas syringae pv. tomato (Pst) although their molecular mechanisms are largely unknown. In tomato, SlWak1 has been implicated in immunity because its transcript abundance increases significantly in leaves after treatment with the flagellin-derived peptides flg22 and flgII-28, which activate the receptors Fls2 and Fls3, respectively. We generated two SlWak1 tomato mutants (Δwak1) using CRISPR/Cas9 and investigated the role of SlWak1 in tomato-Pst interactions. PTI activated in the apoplast by flg22 or flgII-28 was compromised in Δwak1 plants but PTI at the leaf surface was unaffected. The Δwak1 plants developed fewer callose deposits than wild-type plants but retained the ability to generate reactive oxygen species and activate MAPKs in response to flg22 and flgII-28. The induction of Wak1 gene expression by flg22 and flgII-28 was greatly reduced in a tomato mutant lacking Fls2 and Fls3 but induction of Fls3 gene expression by flgII-28 was unaffected in Δwak1 plants. After Pst inoculation, Δwak1 plants developed disease symptoms more slowly than Δfls2.1/fls2.2/fls3 mutant plants, although both plants ultimately were similarly susceptible. SlWak1 co-immunoprecipitated with both Fls2 and Fls3 independently of flg22/flgII-28 or Bak1. These observations suggest that SlWak1 acts in a complex with Fls2/Fls3 and plays an important role at later stages of the PTI in the apoplast.

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