The Parasite Intraerythrocytic Cycle and Human Circadian Cycle are Coupled During Malaria Infection

During infections with malaria parasites P. vivax, patients exhibit rhythmic fevers every 48 hours.  These fever cycles correspond with the time parasites take to traverse the Intraerythrocytic Cycle (IEC) and may be guided by a parasite-intrinsic clock.  Different species of Plasmodia have cycle times that are multiples of 24 hours, suggesting they may be coordinated with the host circadian clock. We utilized an ex vivo culture of whole blood from patients infected with P. vivax to examine the dynamics of the host circadian transcriptome and the parasite IEC transcriptome.  Transcriptome dynamics revealed that the phases of the host circadian cycle and the parasite IEC were correlated across multiple patients, suggesting that the cycles are coupled.  In mouse model systems, host-parasite cycle coupling appears to provide a selective advantage for the parasite.  Thus, understanding how host and parasite cycles are coupled in humans could enable anti-malarial therapies that disrupt this coupling. This was a minimal risk study enrolling ten Thai adults diagnosed with Plasmodium vivax infection by rapid diagnostic test or microscopy at various medical facilities in Na Chaluai and Buntharik Districts in Ubon Ratchathani Province, Thailand, between September and November, 2016. Those meeting initial inclusion criteria (age >18 years) and exclusion criteria (no signs/symptoms of severe malaria, no antimalarial use in the past 4 weeks and not pregnant), underwent venipuncture for peripheral blood smear and complete blood count. Whole blood samples were drawn from each subject with hematocrit levels that exceeded 25%, a parasitemia level at least 0.1% and the parasite population that was well-aligned in their IEC stage at early trophozoite only or with the majority (>80%) in the same stage, either early trophozoites or late trophozoites. Whole blood samples were cultured ex vivo over the subsequent 48 hours and subsamples were flash frozen approximately every 3 hours. RNA was then isolated from the whole blood samples, which included a mixture of human mRNA from PBMCs and parasite RNA from infected RBCs. RNA reads were mapped to both human and parasite transcriptomes and transcript abundance was quantified for both organisms at each time point and for each study participant.