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New light on malaria parasite life cycle fuels hope for prevention and treatment

Discoveries made independently by two US research teams reveal insights into key stages of the malaria parasite’s life cycle and could, according to experts, spur development of a vaccine and new drugs against the disease.

One discovery, reported in the 5 January issue of Science by Ana Rodríguez and her colleagues at the Departments of Medical and Molecular Parasitology, and of Pathology at the New York University School of Medicine, relates to the early or infective form of the malaria parasite that is injected into a person by mosquitoes. At this so-called sporozoite stage, the parasite moves quickly to the liver. The researchers have shown that, contrary to current wisdom, sporozoites do not develop in the first liver cell they enter, but rather wander about, puncturing four or five different cells, until they find a ‘‘suitable’’ cell to settle in for a few days.

What’s more, the researchers showed, sporozoites don’t need the little sacs, or membrane vacuoles, that most bacteria and parasites use to protect themselves during entry into a cell until they settle down to develop: they can also ‘‘choose’’ to penetrate cells directly.

After the sporozoite elects its final liver cell to squat in, the research team observed, it spends a few days replicating into thousands of so-called merozoites, that eventually burst out of the liver cell to invade blood cells. It is the repeated invasion and rupture of blood cells by merozoites that causes the cyclical fever typical of malaria.

Malaria researcher Stephen Hoffman of the US Naval Medical Research Institute in Rockville, Maryland, says this research represents ‘‘a very elegant expansion of our understanding of the liver stage of the parasite’s life cycle’’.

Dr Rodríguez and her colleagues believe that the ‘‘sporozoite migration’’ through several liver cells that they have witnessed may be essential for the parasite to proceed to the merozoite stage of its life cycle.

Other members of the team, including malaria research pioneers Ruth and Victor Nussenzweig, first saw this migrating behaviour in a video microscopy film they had made in 1989, but were unsure how to interpret it. Dr Rodríguez joined the team last year and she and a colleague, Maria Mota, conducted a series of painstaking lab experiments that confirmed the validity of the finding. They observed, too, that in most instances the sporozoite’s hit-and-run behaviour lethally damaged only a minority of liver cells. Most cells survived. They also demonstrated that this behaviour is seen not only with species of the malaria parasite that infect animals, as the video showed, but also with Plasmodium falciparum, the most deadly species that infects humans.

In a comment to the Bulletin, Dr Hoffman said: ‘‘The liver is the ideal target for drugs and vaccines to prevent malaria ... because the liver stage is the longest single stage in the parasite’s life cycle. The parasite takes at least five and a half days to develop from entry into the liver into the stages that are released into the blood. And during those five and a half days the patient is not ill. So it’s a tremendously important window to attack the parasite. But it is extremely difficult to study the liver stages, so I really welcome the Rodríguez discovery.’’

In a remarkable month for malaria research, another US research team, headed by Daniel E. Goldberg, Professor of Medicine and Molecular Microbiology in the Howard Hughes Medical Institute at the Washington University School of Medicine, St Louis, reported another discovery related to the malaria parasite’s life cycle.

In the 2 January issue of the Proceedings of the National Academy of Sciences, the St Louis team described work showing that when merozoites break out of red blood cells they do so in little sacs, or ‘‘parasitophorous vacuolar membraneenclosed merozoite structures’’ (PEMS). Once the PEMS are outside the red blood cell, the researchers showed, the merozoites can be trapped within the PEMS by treating the PEMS with a chemical called E64, a so-called ‘‘protease inhibitor’’. E64 appears to block the merozoites’ mechanism for escaping the PEMS, so preventing the invasion of new red blood cells. Similar enzyme inhibitors are used as part of the triple therapy against AIDS.

If this laboratory finding can be confirmed, it could, Dr Goldberg believes, offer a new route for developing drugs to prevent full-blown malaria disease.

Robert Walgate
London