Authors

Discussion

The first replication, inside the mammalian host, of Plasmodium parasites takes place in the liver. Blocking parasites at this stage protects from disease, yet, very little is known about host-parasite interactions during this crucial phase. We examine how host-parasite interactions mediate the transition from the liver to blood-stage replication. Specifically, we test whether blood-stage replication is initiated from parasites that egress from the liver in a synchronous burst and at a specific time-of-day. Host feeding-fasting rhythms set the schedule for asexual replication in the blood and that parasites developing in the liver are exposed to these rhythms because the liver is responsible for metabolic rhythms. Thus, we hypothesised that by following liver rhythms, parasites could egress from the liver at the manner that initiates blood-stage replication “on time”. Our experiments used several genotypes of P. chabaudi to test: i) if parasites align the initiation of blood-stage replication with host rhythms driven by feeding/fasting cycles or circadian clocks; and ii) the manner by which parasites initiate  blood-stage replication maximises replication during the acute phase of infection. First, we reveal that both P. chabaudi genotypes tested differ in the duration of the liver-phase but both accumulate in the blood throughout an extended period (~16 to 20 hours). The same pattern of blood stage accumulation occurred independently of host feeding/fasting rhythms and regardless of whether hosts had circadian clocks of not. Second, we reveal that overall replication during the acute phase is not influenced by whether parasites accumulate in the blood over an extended period or in a synchronised burst. Our findings suggest that constraints imposed by development in the liver enforce asynchronous egress from the liver, preventing blood stage replication starting “on time” but that parasites overcome this by rapidly scheduling blood stage replication to align with host feeding/fasting rhythms. Understanding the evolutionary limits on the strategies parasites have evolved to exploit their hosts may open new opportunities for disease control. For example, unlike disrupting time-keeping in the blood stage, disrupting time keeping liver is unlikely to affect parasite fitness.