The Cinderella syndrome: why do malaria-infected cells burst at midnight?

Abstract

An interesting quirk of many malaria infections is that all parasites within a host - millions of them - progress through their cell cycle synchronously. This surprising coordination has long been recognized, yet there is little understanding of what controls it or why it has evolved. Interestingly, the conventional explanation for coordinated development in other parasite species does not seem to apply here. We argue that for malaria parasites, a critical question has yet to be answered: is the coordination due to parasites bursting at the same time or at a particular time? We explicitly delineate these fundamentally different scenarios, possible underlying mechanistic explanations and evolutionary drivers, and discuss the existing corroborating data and key evidence needed to solve this evolutionary mystery.

Figure 1

The diversity of mammalian Plasmodium cycles. Circle length indicates cell cycle length; small open points show the end of one 24-h period. Species names inside the inner (green) circle have 24-h cycles, species names inside the middle (blue) circle have 48-h cycles, and species in the outer (black) circle have 72-h cycles. Species infecting rodents are marked with an asterisk (*); all other species infect primates. Species with non-24-h cycles are underlined and shown at the appropriate point on their cycle. (Plasmodium berghei and Plasmodium yoelii are the only species thought to develop asynchronously.) Cycle times are assembled from , , , , .

Figure I

Two developmental ‘traits’. (a) There may be an advantage to all parasites within an infection progressing through the cell cycle in synchrony. (b) Alternatively, there may be an advantage to timing, where transitions to different developmental stages occur at specific times of day. Of course, both traits may be advantageous independently or may be correlated, for example, if parasites use a host circadian cue as a signal to coordinate bursting.

Figure II

Physical and physiological constraints on cell cycles. The physical processes of RBC invasion and parasite replication take time, meaning that merozoite release cannot happen before a time, t₀. Although malaria parasites complete all nuclear divisions prior to cellular division (making the process more efficient), increasing the number of merozoites produced could increase the time required until a mature schizont is ready to burst. Plasmodium species that produce different numbers of merozoites may therefore have different values of t₀. At the other end of the spectrum, once the nuclear divisions have been completed, there may be an upper limit on bursting time, t₁, as parasites may be constrained by passive processes that cause bursting, through deterioration of the infected RBC or bursting under osmotic stress . The difference between times t₀ and t₁ define the window of opportunity during which parasites can burst from infected RBCs.