Circadian rhythmicity in murine blood: Electrical effects of malaria infection and anemia

Abstract

Circadian rhythms are biological adaptations to the day-night cycle, whereby cells adapt to changes in the external environment or internal physiology according to the time of day. Whilst many cellular clock mechanisms involve gene expression feedback mechanisms, clocks operate even where gene expression is absent. For example, red blood cells (RBCs) do not have capacity for gene expression, and instead possess an electrophysiological oscillator where cytosolic potassium plays a key role in timekeeping. We examined murine blood under normal conditions as well as in two perturbed states, malaria infection and induced anemia, to assess changes in baseline cellular electrophysiology and its implications for the electrophysiological oscillator. Blood samples were analyzed at 4-h intervals over 2 days by dielectrophoresis, and microscopic determination of parasitemia. We found that cytoplasmic conductivity (indicating the concentration of free ions in the cytoplasm and related to the membrane potential) exhibited circadian rhythmic behavior in all three cases (control, malaria and anemia). Compared to control samples, cytoplasm conductivity was decreased in the anemia group, whilst malaria-infected samples were in antiphase to control. Furthermore, we identified rhythmic behavior in membrane capacitance of malaria infected cells that was not replicated in the other samples. Finally, we reveal the historically famous rhythmicity of malaria parasite replication is in phase with cytoplasm conductivity. Our findings suggest the electrophysiological oscillator can impact on malaria parasite replication and/or is vulnerable to perturbation by rhythmic parasite activities.

The surface conductance of red blood cells and platelets is modulated by the cell membrane potential

“…By fitting the observed DEP behaviour over a range of frequencies -typically from the kHz to MHz range -with a best-fit curve from the HUGHES Clausius-Mossotti factor, it is possible to estimate the conductance and capacitance of the cell membrane, and the conductivity and (at sufficiently high frequencies) permittivity of the cytoplasm [3]. This has been used to characterise a wide range of cells over many decades, including myocytes [4], cancer cells [5][6][7][8][9][10], cell-drug interaction [11,12], macrophage activation [13], malarial infection [14,15] and stem cell differentiation [16][17][18][19][20].…”

Clockwork intruders: Do parasites manipulate their hostsʼ circadian rhythms?

“…Namely, the electrical capacitance of the membrane gains a rhythm, and rhythms of electrical conductivity of the cytoplasm are phase-shifted ( Fig. 1 C), aligning to the rhythms of parasitemia caused by the IDC ( Labeed et al, 2022 ).…”

“…On one hand, decreased clock gene transcription levels and running wheel behavior ( Rijo-Ferreira et al, 2018 ) could easily be attributed to the inflammatory response. On the other hand, recent findings on the alteration of electrophysiological rhythms of RBCs ( Labeed et al, 2022 ) could point to a more specific and direct effect of the parasite. More studies are still required to determine whether this is a manipulation by the parasite, or an adapted response from the host to the parasite’s rhythmic replication cycles.…”