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Written by Associate Professor Ashraful Haque, University of Melbourne

Malaria is a devastating disease which has taken millions of human lives, often young children, and even influenced human evolution. Yet, this disease is caused by the tiniest of parasites. So tiny in fact, that the parasite, called Plasmodium, is composed of a single cell. This stands in marked contrast to your body, which is composed of trillions of cells (that’s at least 12 zeros)!

Malaria parasites are transmitted through the bite of a specific type of mosquito, primarily found in Africa and Asia. Once inside the body, the parasites eventually enter the bloodstream, where they take over the most common cell in your blood, the oxygen-carrying red blood cell. Inside these adopted homes, a single malaria parasite starts renovating and re-purposing the cell for its own singular goal of reproducing itself up to 32 times.

The renovation and reproduction process takes time, a specific amount of time that tracks with the length of a day on Earth. Some malaria parasite species take 48 hours to complete this cycle, some 72 hours, with other species completing the feat in 24 hours. See a pattern? Yes, for reasons that remains unclear, malaria parasites seem to observe a body clock in red blood cells that is Earth-specific, or “circadian”, similar to the rhythms that govern much of the biology in our own bodies.

So, why is this body clock important? Well, the faster parasites renovate and reproduce, the faster their population grows inside the body. This is critical, because the more parasites there are in the body, the greater the chances of experiencing severe and possibly lethal symptoms before medical teams have had a chance to administer anti-malarial drugs. 

The most lethal malaria parasite, Plasmodium falciparum, is thought to have a body clock of 48 hours in human red blood cells. But is the parasite’s body clock really constant? Could our bodies stretch or slow time down for parasites, to obstruct the process of renovation? Research suggests that this is the case, another way in which the body try to minimise the damage caused by these parasites.

In a research published in the peer-reviewed journal mBio, conducted in collaboration with mathematical modellers at The Kirby Institute, UNSW, we found that when the body experiences “whole body inflammation”, a process often observed in bloodstream infections, the composition of the blood changes in a way that renders it less hospitable for renovating parasites. In fact, molecules appear in the plasma, the liquid medium surrounding red blood cells, which slow down the pace at which parasite renovates. 

Our mathematical assessments suggested that this change could lead to a significant increase – up to 70 per cent – in the time needed for renovation and reproduction (2)! While it might not sound like much, slowing down the growth of parasite population could buy the body precious time, time that could be essential to get to hospital in time to receive life-saving drugs.

In our research, not only did we watch the parasites as they attempted to renovate and reproduce, we also used advanced methods to determine if parasites could detect and respond to changes inside the body. This approach, called “single-cell transcriptomics” is a way to study every gene inside the parasite, to determine if it is active or not. 

Remarkably, we observed that the parasites rapidly sensed and responded to the inhospitable environment, within as little as four hours. This rapid response triggered a massive transformation inside the parasite. This discovery highlights a reciprocal “sense and response” process between the body and the infecting malaria parasites. Just as our immune systems are capable of sensing, slowing down and removing parasites, parasites, in turn, may be capable of detecting the body’s attempts to stop them in their tracks. 

Our research is a reminder that we must consider the malaria parasite’s ability to swiftly sense and respond to the body’s attempts to kill or obstruct them, either by inflammatory responses, the immune system or antimalarial drugs. Our research, and that of others in recent years (3, 4), emphasise that malaria parasites are not a static enemy. They are highly adaptable in real-time, able to shift and move in response to the threats they perceive inside the body.

1. Lansink LIM, Skinner OP, Engel JA, Lee HJ, Soon MSF, Williams CG, et al. Systemic host inflammation induces stage-specific transcriptomic modification and slower maturation in malaria parasites. mBio. 2023;14(4):e0112923 (https://doi.org/10.1128/mbio.01129-23)
2. Khoury DS, Cromer D, Akter J, Sebina I, Elliott T, Thomas BS, et al. Host-mediated impairment of parasite maturation during blood-stage Plasmodium infection. Proc Natl Acad Sci U S A. 2017;114(29):7701-6. (https://doi.org/10.1073/pnas.161893911)
3. Mancio-Silva L, Slavic K, Grilo Ruivo MT, Grosso AR, Modrzynska KK, Vera IM, et al. Nutrient sensing modulates malaria parasite virulence. Nature. 2017;547(7662):213-6.
4. Smith LM, Motta FC, Chopra G, Moch JK, Nerem RR, Cummins B, et al. An intrinsic oscillator drives the blood stage cycle of the malaria parasite Plasmodium falciparum. Science. 2020;368(6492):754-9.