Why some tolerate malaria better than others

A team of researchers from Portugal and the US has shown how an antioxidant enzyme that occurs naturally in the body plays an important role in helping individuals to tolerate the malaria-causing parasite Plasmodium. The findings, funded in part by the EU and published in the journal Proceedings of the National Academy of Sciences (PNAS), offer a new approach to treatment of this deadly disease.

The study was an outcome of the Xenome (Engineering of the porcine genome for xenotransplantation studies in primates: a step towards clinical application) project, funded with EUR 9.9 million through the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6) to investigate new health applications for knowledge gained in the field of genomics.

Malaria is one of the main causes of premature death worldwide, but compared to the vast number of Plasmodium-infected individuals a relatively small percentage (1%-2%) die from the disease. It is, after all, in the interests of the parasite to keep its host alive. Whether a person succumbs to the infection is widely believed to depend on that individual's resistance to infection and also their ability to tolerate infection. But the mechanism behind such tolerance has until now been poorly understood.

A team of researchers led by Miguel Soares of the Instituto Gulbenkian de Ciência in Portugal studied Plasmodium-infected mice. They showed how the parasite replicates inside red blood cells, causing them to burst and release haemoglobin (the protein that binds oxygen inside the cells) into the blood stream. This freely circulating haemoglobin in turn releases its haem (iron) groups, with sometimes devastating results.

Among the many strategies employed by the mice to counter this effect, the researchers observed that they produce more of the enzyme haem oxygenase 1 (HO-1), which breaks down the haem groups. They found that infected mice expressing high levels of HO-1 were protected from developing severe malaria symptoms. The results were confirmed when the scientists administered the anti-oxidant drug N-acetylcysteine (NAC) to the mice and observed the same protective effect.

The haem/HO-1 system described by the team sheds light on both cerebral and noncerebral forms of severe malaria, including those that lead eventually to multi-organ failure. Importantly, the study also demonstrated that the protective effect of HO-1 against freely circulating haem increases a host's tolerance of Plasmodium infection.

"The antioxidant action of HO-1 is part of the host's natural defence strategy against the malaria parasite," explained Dr Soares. "It affords a potent protective effect against malaria but, astonishingly, does not seem to directly affect the parasite. In some cases the reaction of the host against the parasite can lead to [the] death of the infected host. The protective mechanism afforded by HO-1 allows this host response to kill the parasite without compromising its own survival."

According to Dr Soares, the results of the study indicate that alternative approaches to treating malaria should focus not on killing the parasite directly, "but rather at strengthening the health status of the host, so that the host could kill the parasite and survive." This type of approach "should provide potent protection against severe forms of malaria and thus save lives without favouring the appearance of resistant strains of Plasmodium," he concluded.

The researchers hope that the same strategy will be applied to a range of other infectious diseases.

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