Malaria parasites kill more than a million people every year. These minuscule organisms, belonging to the genus Plasmodium, ensconce themselves inside our red blood cells. They eat our oxygen-carrying haemoglobin protein, and sup on the rich supply of glucose in our blood plasma. Hidden from our immune system within our own cells, they multiply exponentially, inducing anaemia, acidity of the blood, low blood sugar, fluid build-up in the lungs, seizures and blockage of brain capillaries — complications that can kill a person within ten days of being infected by a malaria-carrying mosquito. Until now, we believed that malaria parasites burned the glucose they stole from our plasma using a simple and relatively inefficient process known as glycolysis. After all, why would a parasite bother to extract maximum energy from glucose when abundant free glucose is at hand?

On page 1091 of this issue, however, Daily and colleagues1 show that, in some infections, the parasites behave as if they are starving, cranking up genes involved in energy-harvesting pathways to wring out the maximum burn from the proceeds of their parasitism. Switching on these genes could enable parasites to engage the tricarboxylic acid (TCA) cycle, the cellular motor that burns the leftover fuel from glycolysis to allow energy production to shift into top gear (see Fig. 4 of the paper1 on page 1093). Intriguingly, the different parasite behaviours might correlate with different disease profiles, potentially explaining why different patients experience radically different symptoms during severe malaria infections.

Without a straightforward, easily accessible animal model for the deadliest malaria species, Plasmodium falciparum, lab work on the disease has been a difficult proposition. In 1976, a seminal paper2 described a method of growing P. falciparum in Petri dishes of glucose-rich human blood with reduced oxygen levels. This method, essentially unchanged, is used in all modern malaria labs; it underpins all quests for a cure, whether they involve drug screens, genetic studies, genome sequencing, immunology, biochemistry or cell biology. Post-genomic studies have painstakingly mapped the expression levels of every gene and the quantities of each encoded protein across the orderly 48-hour part of the life cycle that the parasite executes in red blood cells3,4,5. These studies reinforced the view that genes encoding the proteins required for glycolysis are abundantly expressed during this part of the life cycle. The parasites were all perceived to be marching to a rigid, yet energy-profligate rhythm, apparently oblivious to the world around them — us.

Studying pandas in a zoo is not the same as studying them in the wild. Likewise, these lab-based in vitro culture studies might not accurately reflect how the parasites behave in their natural environment. Hence the approach adopted by Daily et al.1, who took blood from patients infected with P. falciparum in Senegal, and used microarray DNA chip technology to generate a parasite gene-expression profile for each patient. In many patients, parasite profiles were the same as those observed in lab-cultured parasites — the parasites seemed to be running on energy derived from glycolysis.

But parasites from two other groups of patients exhibited very different, and hitherto unseen, gene-expression profiles. In one group, the parasites had upregulated stress-response genes, probably to cope with host immune pressure. In the other group, they had downregulated the glycolysis genes normally switched on in lab-cultured parasites, but up-regulated genes involved in alternative means of energy generation, a trait seen, for instance, in yeast cells starved of glucose. These results imply that there are physiological differences in the growth of parasite populations in different individuals. In other words, malaria parasites do not always grow in humans as they do in Petri dishes.

The changes in gene expression seen in 'starved' parasites are particularly curious. Two subcellular compartments (organelles) in the malaria parasite, the apicoplast and the mitochondrion, may hold the key to the apparent metabolic switching seen here. The apicoplast is a chloroplast-like organelle thought to have been originally photosynthetic but now retained for the biosynthesis of lipid building-blocks known as fatty acids6. Mitochondria harbour the enzymes of the TCA cycle as well as an energy-generating electron-transport chain that together finish the incineration of glucose and other substrates to increase energy yields. Both apicoplast fatty-acid synthesis and mitochondrial energy-production genes are dramatically upregulated in the 'starved' parasites1.

What drives these differences in gene expression? Although apicoplast fatty-acid biosynthesis is essential for successful infection7, its exact role is unclear because malaria parasites can scavenge fatty acids from their host. Upregulation of the apicoplast pathway for fatty-acid synthesis may suggest an increased need for fatty acids or a short supply of them from hosts. Similarly, upregulation of pathways involved in efficient mitochondrial energy generation implies either an increased need for energy or a reduced supply of glucose for glycolysis. A recent study8 on laboratory-grown parasites concluded that mitochondria are not required for energy generation. But Daily and colleagues' discovery of the upregulation of genes involved in these mitochondrial energy-synthesizing pathways suggests that this may not always be the case.

The findings presented here raise various questions. What causes the different parasite gene-expression profiles? Do these profiles reflect distinct temporal stages of in vivo parasite development, or are they discrete snapshots of an intense battle between parasite and host? Are parasites initiating these differences, or are they merely reacting to cues from the host? Patient factors such as blood glucose levels, the amount of haemoglobin and the number of parasites in the blood do not seem to be linked to the starvation response. If there is an environmental cue, it is a subtle one.

One caveat in interpreting Daily and colleagues' results1 is that gene upregulation doesn't always translate to metabolic upregulation; biochemical validation of actual metabolic switching is needed, and this will probably require elicitation of the starvation response in laboratory-grown parasites. At a more practical level, it will be important to understand whether different parasite gene-expression profiles are linked to the spectrum of disease experienced by patients with malaria, which, in turn, may point to more effective treatments. For example, drugs targeting fatty-acid biosynthesis and the mitochondrial electron-transport chain8,9 should be especially effective against parasites in starvation mode.

We have come a long way in understanding malaria and its causes. But the findings presented by Daily et al.1 show that we are just beginning to comprehend the complexity of the metabolic engine that drives these parasites.

Figure 1: In the blood.
figure 1

PHOTOTAKE INC./ALAMY G. G. VAN DOOREN/G. I. MCFADDEN

An electron micrograph of red blood cells infected with Plasmodium falciparum. Inset, fluorescently labelled invasive parasites revealing their mitochondrion (green), apicoplast (red) and nucleus (blue). Inset, ×1,250.

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