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

Abstract

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.

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

“…To identify metabolites whose rhythms correspond to the timing of host feeding and the IDC schedule, we compared four groups of malaria infections in mice that were either wild type (WT) C57BL/6J strain or Per1/2-null (Period 1 and Period 2) circadian clock-disrupted mice. Per1/2-null mice have an impaired canonical clock (Transcription Translation Feedback Loop, TTFL) and exhibit no circadian rhythms in physiology or behaviour when kept in constant darkness (Bae et al 2001, Maywood et al 2014; O’Donnell et al 2019). We generated 3 different groups of hosts whose feeding-fasting rhythms differed with respect to the light:dark cycle and whether they had an intact TTFL clock, and a 4 th group of hosts which lacked both feeding rhythms and an intact TTFL clock (Fig 1B).…”

“…Some parasites use their own circadian clocks to control metabolism (Rijo-Ferreira et al 2017), and virulence (Hevia et al 2015), suggesting that host rhythms are a selective (evolutionary) driver of parasite rhythms. Host rhythms have fitness consequences for malaria ( Plasmodium ) parasites (O’Donnell et al 2011, 2013), whose rhythmicity in development during blood-stage replication is aligned with the timing of host feeding-fasting cycles (Hirako et al 2018, Prior et al 2018, O’Donnell et al 2020).…”

“…Per1/2-null mice were housed in continuous darkness (DD) and either experienced cycles of 12-hours with food followed by 12 h without access to food (TRF, time restricted feeding,) or given constant access to food (ALF, ad-libitum feeding). The parasite IDC is rhythmic in DF, LF and TRF mice but not ALF mice (O’Donnell et al 2019), and so, the IDC rhythm is substantially dampened. (C) Metabolites that were significantly rhythmic in DF, LF and TRF mice (highlighted in red), but not in ALF mice, were sought.…”

“…Malaria parasites are able to keep time (Rijo-Ferreira et al 2020, Subhudhi et al 2020) and organise their IDC schedule to coordinate with an aspect of host feeding-fasting rhythms (Hirako et al 2018, Prior et al 2018), but not the act of eating itself (Rijo-Ferreira et al 2020), or metabolic processes directly controlled by canonical host circadian clocks (O’Donnell et al 2019). Coordination with host feeding-fasting rhythms may allow parasites to couple the nutritional needs of each IDC stage with circadian fluctuations in the concentrations of nutrients in the blood (Prior et al 2020).…”

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

“…Hosts had access to food constantly (all-day fed) or only during a window of 8 h per day (food in 09:00/food out 17:00 UTC; time restricted fed; TRF). Note, TRF protocols do not lead to caloric restriction or a loss in body mass [ 10 ]. Food was provided/removed by changing the cage lid and sweeping the cage for stray pellets at the times of removal and mice in the all-day fed group experienced the same disturbance.…”