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

Abstract

Malaria parasites complete their intra-erythrocytic developmental cycle (IDC) in multiples of 24 hours (depending on the species), suggesting a circadian basis to the asexual cell cycle, but the mechanism controlling this periodicity is unknown.Combining in vivo and in vitro approaches using rodent and human malaria parasites, we reveal that: (i) 57% of Plasmodium chabaudi genes exhibit 24 h "circadian" periodicity in transcription; (ii) 58% of these genes lose transcriptional rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 9% of Plasmodium falciparum genes show circadian transcription under free-running conditions; (iv) Serpentine receptor 10 (SR10) has a circadian transcription profile and disrupting it in rodent malaria parasites shortens the IDC by 2-3 hours; (v) Multiple processes including DNA replication and the ubiquitin and proteasome pathways are affected by loss of coordination with host rhythms and by disruption of SR10. Our results show that malaria parasites are at least partly responsible for scheduling their IDCs explaining the fitness benefits of coordination with host rhythms.Daily fluctuations in environmental parameters such as light and temperature are assumed to select for the evolution of circadian clocks. In many organisms, circadian RESULTSThe transcriptome of Plasmodium chabaudi responds to host circadian rhythms Transcriptome analyses of time series RNA sequencing datasets were performed with P.chabaudi parasites from infections that were in synchrony (phase aligned; "host rhythm matched") and out of synchrony (out of phase; "host rhythm mismatched") with host circadian rhythms (for details see methods section). Briefly, a controlled number of infected red blood cells (RBC) were sub-inoculated from donor mice into two groups of recipient mice (n = 43 per group) each housed under different light regimes (12 hours (h)

Periodic Parasites and Daily Host Rhythms

“…of parasites in vivo are inevitably confounded by synchronous development throughout the IDC of 24 h. Using P. falciparum would overcome some of these obstacles because its IDC duration is 48 h and it can be cultivated in vitro (Subudhi et al, 2019). Thus, experiments in which constant (''free-running'') conditions are generated by either not replenishing or continuously replenishing media could use P. falciparum to test for 24 h rhythms in gene expression and protein production, as well as temperature compensation.…”

The Complex Interplay of Parasites, Their Hosts, and Circadian Clocks

“…A recent report has addressed a similar question in Plasmodium (Subudhi et al, 2019). Mice infected with P. chabaudi (which displays a 24 h development cycle in RBCs) were housed under a light-dark cycle, and blood sampled over 30 h was used for RNA sequencing: over 5,000 P. chabaudi transcripts displayed ∼24 h rhythms.…”

“…A followup study showed that this mismatch effect does not depend on either the developmental stage of the parasite used for infection or on the route of infection, and has an impact at early infection stages (O'Donnell et al, 2013). A misalignment of the P. chabaudi and host rhythms also impacted rhythmic parasite genes, and led to a reduced development cycle period (Subudhi et al, 2019).…”