Edinburgh Research Explorer Malaria parasites regulate the duration of the intra-erythrocytic cycle via serpentine receptor 10 and coordinate development with host daily rhythms

Malaria parasites complete their intra-erythrocytic developmental cycle (IDC) in multiples of 24 h suggesting a circadian basis, but the mechanism controlling this periodicity is unknown. Combining in vivo and in vitro approaches utilizing rodent and human malaria parasites, we reveal that: (i) 57% of Plasmodium chabaudi genes exhibit daily rhythms in transcription; (ii) 58% of these genes lose transcriptional rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 6% of Plasmodium falciparum genes show 24 h rhythms in expression under free-running conditions; (iv) Serpentine receptor 10 (SR10) has a 24 h transcriptional rhythm and disrupting it in rodent malaria parasites shortens the IDC by 2-3 h; (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 reveal malaria parasites are at least partly responsible for scheduling the IDC and coordinating their development with host daily rhythms. machinery are expressed maximally (ZT 16.5 – 19.5). In a separate analysis, we compared two consecutive time points (ZT 22.5 and ZT 1.5) within each strain as controls, with an expectation of less differential alternative splicing events within compared to between wild type and sr10 KO parasites for the same time point. Differential alternative splicing events in terms of differential exon usage were detected using the DEXSeq program v 1.20.02 68 with modi fi ed scripts as reported in Yeoh et al. 69 . The p value signi fi cance level was set to 0.05 for the identi fi cation of differential exon usage. Comparison was made between P. chabaudi wild type and the SR10 knock out strains for two time points i.e., Day 3, ZT 21 and Day 3, ZT 0/24 post-infection. For these two time points, RNAseq read depth was increased by performing additional rounds of sequencing in order to detect AS events more reliably. biological

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