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. 2024 May 8;17(5):e13696.
doi: 10.1111/eva.13696. eCollection 2024 May.

Virulence is associated with daily rhythms in the within-host replication of the malaria parasite Plasmodium chabaudi

Alíz T Y Owolabi  1 , Petra Schneider  1 , Sarah E Reece  1
Affiliations

Virulence is associated with daily rhythms in the within-host replication of the malaria parasite Plasmodium chabaudi

Alíz T Y Owolabi et al. Evol Appl. .

Abstract

Most malaria (Plasmodium spp.) parasite species undergo asexual replication synchronously within the red blood cells of their vertebrate host. Rhythmicity in this intraerythrocytic developmental cycle (IDC) enables parasites to maximise exploitation of the host and align transmission activities with the time of day that mosquito vectors blood feed. The IDC is also responsible for the major pathologies associated with malaria, and plasticity in the parasite's rhythm can confer tolerance to antimalarial drugs. Both the severity of infection (virulence) and synchrony of the IDC vary across species and between genotypes of Plasmodium; however, this variation is poorly understood. The theory predicts that virulence and IDC synchrony are negatively correlated, and we tested this hypothesis using two closely related genotypes of the rodent malaria model Plasmodium chabaudi that differ markedly in virulence. We also test the predictions that, in response to perturbations to the timing (phase) of the IDC schedule relative to the phase of host rhythms (misalignment), the virulent parasite genotype recovers the correct phase relationship faster, incurs less fitness losses and so hosts benefit less from misalignment when infected with a virulent genotype. Our predictions are partially supported by results suggesting that the virulent parasite genotype is less synchronous in some circumstances and recovers faster from misalignment. While hosts were less anaemic when infected by misaligned parasites, the extent of this benefit did not depend on parasite virulence. Overall, our results suggest that interventions to perturb the alignment between the IDC schedule, and host rhythms and increase synchrony between parasites within each IDC, could alleviate disease symptoms. However, virulent parasites, which are better at withstanding conventional antimalarial treatment, would also be intrinsically better able to tolerate such interventions.

Keywords: asexual replication; circadian misalignment; circadian rhythm; host–parasite interactions; infection severity; intraerythrocytic developmental cycle.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Experimental design. We infected experimental mice, housed in the standard photoschedule (green, LD), with 107 ring‐stage parasites of either the relatively avirulent Plasmodium chabaudi CW‐0 (yellow) or the more virulent CW‐VIR (pink) genotype. For each genotype, parasites originated from donor mice housed in the standard photoschedule (green, LD) for ‘aligned’ groups or housed in the reversed photoschedule (grey, DL) for ‘misaligned’ groups where the alignment of the intraerythrocytic developmental cycle (IDC) to the rhythms of experimental hosts was perturbed. We replicated these four treatment groups in two cohorts, using the‘Fitness cohort’ to assess parasite performance and disease severity and the ‘Rhythms cohort’ to characterise the IDC schedule.
FIGURE 2
FIGURE 2
Parasite fitness proxies. The impact of alignment (solid lines) and misalignment (dashed lines) on CW‐0 (yellow circles) and CW‐VIR (pink squares) for measures of parasite performance (mean ± SEM): (a) total parasite density dynamics and (b) cumulative total parasite density, (c) daily gametocyte dynamics and (d) cumulative gametocyte density. Cumulative densities are derived from summing data for individual hosts from days 3 to 16 PI.
FIGURE 3
FIGURE 3
Disease severity proxies. Means ± SEM for aligned (solid lines) and misaligned (dashed lines) parasites of genotypes CW‐0 (yellow circles) and CW‐VIR (pink squares): (a) Mouse weights from days −1 to 16 post‐infection (PI); (b) Cumulative weights, derived from summing data for individual hosts from day 3 to 16 PI; (c) Red blood cell (RBC) density per mL of blood from day −1 to 16 PI; and (d) Cumulative RBCs, derived from summing data for individual hosts from day 3 to 16 PI.
FIGURE 4
FIGURE 4
Intraerythrocytic developmental cycle (IDC) rhythms. Means ± SEM for aligned (solid lines) and misaligned (dashed lines) parasites of genotypes CW‐0 (yellow circles) and CW‐VIR (pink squares): (a) proportion of parasites at ring stage, (b) amplitude, (c) period and (d) peak ring phase. Grey shading represents the dark phase of the circadian cycle (i.e. the host's active phase).
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