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Adaptive Periodicity in the Infectivity of Malaria Gametocytes to Mosquitoes

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Adaptive Periodicity in the Infectivity of Malaria Gametocytes to Mosquitoes

Petra Schneider et al. Proc Biol Sci.

Abstract

Daily rhythms in behaviour, physiology and molecular processes are expected to enable organisms to appropriately schedule activities according to consequences of the daily rotation of the Earth. For parasites, this includes capitalizing on periodicity in transmission opportunities and for hosts/vectors, this may select for rhythms in immune defence. We examine rhythms in the density and infectivity of transmission forms (gametocytes) of rodent malaria parasites in the host's blood, parasite development inside mosquito vectors and potential for onwards transmission. Furthermore, we simultaneously test whether mosquitoes exhibit rhythms in susceptibility. We reveal that at night, gametocytes are twice as infective, despite being less numerous in the blood. Enhanced infectiousness at night interacts with mosquito rhythms to increase sporozoite burdens fourfold when mosquitoes feed during their rest phase. Thus, changes in mosquito biting time (owing to bed nets) may render gametocytes less infective, but this is compensated for by the greater mosquito susceptibility.

Keywords: Hawking hypothesis; Plasmodium chabaudi; circadian rhythm; periodicity; transmission strategy; vector.

Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
Experimental design. We infected 80 mice (over two blocks) with ring stages of P. chabaudi (genotype AS) at ZT3 to ensure parasite rhythms were in phase with the host's rhythms in all treatment groups [21,23]. At ZT8 (green), 40 mice were fed to 40 cages of mosquitoes experiencing their day (ZT8; solid arrow) or night (ZT16; dotted arrow) and we repeated this at ZT16 for the other 40 mice (blue). Gametocyte metrics were quantified in the two groups of mice just before exposure to mosquitoes and oocysts and sporozoites were followed in the four groups of mosquitoes. All feeds (i.e. at both ZT8 and ZT16) were performed in the dark to prevent unexpected light exposure to mosquitoes, which is known to affect biting behaviours and rhythms in gene expression [24,25].
Figure 2.
Figure 2.
Gametocyte densities circulating in host blood are lower during the night time (ZT16) than the daytime (ZT8). n = 40 mice per time point.
Figure 3.
Figure 3.
Night-fed mosquitoes are less likely to be infected (a) but oocyst burdens are not influenced by time of day for either party (b). Data presented are mean ± s.e.m. for the proportion of mosquitoes that are infected with oocysts (a) and oocyst burdens for all fed mosquitoes regardless of whether infected or not (b). Groups are: daytime (ZT8; closed symbols) and night time (ZT16; open symbols) feeding mosquitoes that fed on mice experiencing their day (ZT8; green) or night (ZT16; blue). Data in (b) are square root transformed to meet statistical model assumptions for analysis.
Figure 4.
Figure 4.
Gametocytes are more infective at night. Gametocytes taken up from hosts experiencing their night (ZT16; blue) are more likely to form oocysts than those taken up during the daytime (ZT8; green), regardless of time of day for mosquitoes (ZT8 closed and ZT16 open symbols). Gametocyte densities for each host are plotted against their corresponding mean oocyst burdens (square root transformed to meet model assumptions), and the fits are from linear regressions.
Figure 5.
Figure 5.
Parasite and mosquito time of day do not affect sporozoite prevalence (a) but do affect sporozoite burdens (b). Each sample consisted of a pool of five mosquitoes that blood fed on the same mouse (four samples per mouse): a positive pool requires that at least one of five mosquitoes were infected with sporozoites. Data presented are the mean ± s.e.m. for the proportion of sporozoite positive pools (a) and sporozoite burdens for all fed mosquitoes (b). Groups are: daytime (ZT8; closed symbols) and night time (ZT16; open symbols) feeding mosquitoes that fed on mice experiencing their day (ZT8; green) or night (ZT16; blue). Data in (b) are square root transformed to meet model assumptions.
Figure 6.
Figure 6.
Dynamics of gametocyte development. A new cohort of gametocytes starts developing at every schizogony (approx. ZT17) and P. chabaudi gametocytes are thought to require approximately 36 h from schizogony to reach maturity (i.e. begin to mature at approx. ZT2 on second day) and remain mature (i.e. infective) for 12–18 h (i.e. up to ZT17–23 on the second day) before senescing [12,35]. The half-life of a mature gametocyte is approximately 14 h and most gametocytes are cleared by 60 h post schizogony (i.e. ZT12 on the third day [12,35]. During our experiment, we collected parasites at daytime (ZT8; green line) and night time (ZT16; blue line), thus sampling three cohorts of gametocytes (A–C), and our RT-qPCR assays detect gametocytes from 30 to 35 h post schizogony onwards, and thus, they are mature and only from cohorts A and B [26]. At ZT8, gametocytes comprised those produced on day 3 and not yet infective and not detected (cohort C); those produced on day 2 and reaching peak maturity (cohort B); and produced on day 1 and senescing (cohort A). Whereas, at ZT16, gametocytes were not yet infective and not detected (cohort C); at peak maturity (cohort B) and mostly cleared (cohort A). If more of cohort A's gametocytes are lost by ZT16, this could explain the lower density and the higher per-gametocyte infectivity observed at ZT16. Furthermore, if a cohort of gametocytes gradually attains maturity from approximately 36 h of age, more of cohort B's gametocytes will be infective at ZT16 than ZT8. The contributions of cycles of maturation, senescence and mortality may be further complicated by variable investment in gametocytes in sequential cohorts [36].

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