|Home > Parasite > Features >|
The malaria parasite consumes far more red blood cell haemoglobin than it actually needs as nutrients. Virgilio Lew and colleagues have discovered why: it stops the red blood cell bursting too early.
Plasmodium falciparum parasites cause the most lethal form of malaria in humans. The asexual reproduction cycle of the parasite takes place within red blood cells, well shielded from attack by the immune system. Young parasite forms called merozoites invade red cells, develop, multiply, and, after 48 hours, the infected cells rupture releasing about 20 new merozoites ready to infect other red cells.
During this process, the parasite induces a huge increase in the permeability of the host red blood cell membrane, enabling it to gather nutrients from the bloodstream and to discharge waste products; it also ingests and digests about 70 per cent of the haemoglobin in the red blood cell.
Recent work from two laboratories, involving precise measurements of the changes in host-cell permeability and haemoglobin consumption occurring at different stages of parasite development, brought two major surprises.
Kiaran Kirk, from the Australian National University, Canberra, with Henry Staines and Clive Ellory, from Oxford University, found that if the membrane of an uninfected red blood cell was made as permeable as that of an infected cell, it would burst well before 48 hours.
For an infected cell the problem is even more acute, as the parasite grows to near the size of the original red cell. With such an extra growth inside, how do the infected red cells retain their osmotic stability for the 48 hours required by the parasite to reproduce?
The second surprise came from the work of Hagai Ginsburg and colleagues at the Hebrew University of Jerusalem, Israel. They found that the parasite uses less than 16 per cent of the amino acids produced by the digestion of haemoglobin. More than 84 per cent of the amino acids produced are dumped out of the infected red blood cell through its now permeable membrane.
So why do parasites expend so much energy processing, detoxifying and eliminating the by-products of haemoglobin digestion in such apparently excessive and unnecessary amounts?
To address these questions Virgilio Lew, from the University of Cambridge, modified and extended his earlier mathematical model of red cell homeostasis so that it could be applied to an infected red cell. He factored in the known stage-related changes in host cell membrane permeability, haemoglobin consumption and parasite growth, together with the multiple factors known to influence the volume of the cell.
The model produced an unexpected prediction: that the red blood cell would shrink in volume 16–28 hours after it had been infected, and then would swell for the rest of the cycle. But, contrary to expectations, the cell would not burst before the 48-hour cycle was complete.
To test the model, Teresa Tiffert, also from the University of Cambridge, Ginsburg and Lew measured the distribution of cell volumes in populations of red blood cells infected with Plasmodium falciparum at different stages of the asexual reproduction cycle. The results fully confirmed the volume changes predicted by the model.
So, how does the model answer the fundamental questions posed above? According to the model, the two questions are intimately linked: when the membrane of the red blood cells becomes very permeable, the high concentrations of haemoglobin inside would normally encourage fluid to move in, swelling and bursting the cell. The parasite therefore keeps the cell stable by digesting far more haemoglobin than it needs for its own proteins, the excess being removed from the cell.
This represents a novel adaptive mechanism that ensures the viability of the invaded host cell for the duration of the parasite reproductive cycle. The energy cost may be high, but considering the relentless persistence of malaria, who can doubt the unfortunate evolutionary success of this strategy?
Dr Virgilio Lew is at the Department of Physiology, Development and Neuroscience, University of Cambridge.
Lew VL, Tiffert T, Ginsburg H (2003) Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum-infected red blood cells. Blood 101: 4189-94. Abstract
Page of 2; 2/9/04
[WTD023863] Haemoglobin consumption: Eating to stop bursting.doc