Daily Rhythms of TNFα Expression and Food Intake Regulate Synchrony of Plasmodium Stages with the Host Circadian Cycle

Abstract

The Plasmodium cell cycle, wherein millions of parasites differentiate and proliferate, occurs in synchrony with the vertebrate host's circadian cycle. The underlying mechanisms are unknown. Here we addressed this question in a mouse model of Plasmodium chabaudi infection. Inflammatory gene expression and carbohydrate metabolism are both enhanced in interferon-γ (IFNγ)-primed leukocytes and liver cells from P. chabaudi-infected mice. Tumor necrosis factor α (TNFα) expression oscillates across the host circadian cycle, and increased TNFα correlates with hypoglycemia and a higher frequency of non-replicative ring forms of trophozoites. Conversely, parasites proliferate and acquire biomass during food intake by the host. Importantly, cyclic hypoglycemia is attenuated and synchronization of P. chabaudi stages is disrupted in IFNγ, TNF receptor, or diabetic mice. Hence, the daily rhythm of systemic TNFα production and host food intake set the pace for Plasmodium synchronization with the host's circadian cycle. This mechanism indicates that Plasmodium parasites take advantage of the host's feeding habits.

Within‐host modeling of blood‐stage malaria

“…However, very recent work suggests that host feeding cycles and metabolic processes, and circadian fluctuations in the production of inflammatory cytokines may be involved. 54,55 While synchronized parasite replication is a common feature of human (and some animal) Plasmodium species, it is not universal. Plasmodium berghei for example, a common species studied in mice, will desynchronize over the course of infection.…”

Host circadian clocks do not set the schedule for the within-host replication of malaria parasites

“…Glucose regulation is a tightly controlled process, achieved via the antagonistic effects of the hormones insulin and glucagon, and involves the contribution of several different organs (liver, pancreas) to ameliorate the effects of feeding and fasting. Malaria infection disrupts this balance by pushing blood glucose concentration away from the optimum at the end of the active phase, exacerbating the drop in glucose at this time [10]. This drop, or the rise in blood glucose concentration at the start of the feeding period could either signal time-of-day to parasites and/or enforce a schedule in which only the most glucose demanding IDC stages (late trophozoites and schizonts) can develop during the feeding period.…”

“…The IDC lasts 24 hours (or multiples of 24 hours, depending on the parasite species) and is characterised by progression through distinct developmental stages at particular times-of-day. For example, the timing of P. chabaudi’s IDC transitions are determined by the time-of-day that murine hosts are provided with food [10, 11]. Specifically, parasites remain in early IDC stages when hosts are fasting and complete the IDC at the end of the feeding phase.…”

Disruption of the coordination between host circadian rhythms and malaria parasite development alters the duration of the intraerythrocytic cycle

“…Blood glucose levels are rhythmic during the circadian cycle in mice 26 . This rhythm is exacerbated in malaria-infected mice due to the alterations in energy metabolism experienced by inflammatory leukocytes 12 . Given that completing the IDC is glucose demanding, malaria parasites may be expected to express genes rhythmically to utilize the energy source efficiently.…”

“…Rhythms in host feeding and innate immune responses influence the timing of rhythms in the IDC of rodent malaria parasites 12,13 . Specifically, completion of the IDC, a glucosedemanding process, coincides with host food intake, and quiescence during the early phase of the IDC coincides with the daily nadir in host blood glucose that is exacerbated by the energetic demands of immune responses 12 . However, the extent to which malaria parasites or their hosts are responsible for IDC scheduling is unclear 14 .…”