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Antibiotics for the prevention of malaria

Researchers from Heidelberg and Berlin have shown that if malaria-infected mice are administered an antibiotic, no parasites appear in the blood and the mice are protected from this life-threatening disease. The scientists believe that antibiotics also have the potential to strengthen the human immune system as well as making it possible to provide a natural needle-free vaccination against malaria.

Plasmodium falciparum in blood cells. © University Hospital Heidelberg

In Africa, one million children under the age of six die from malaria every year; this means that on average one child dies every 30 seconds. The World Health Organisation (WHO) estimates that in 2007 around 451 million people were infected with Malaria tropica, which is transmitted by Plasmodium falciparum and is one of the most dangerous types of malaria. The WHO also estimates that globally, over three billion people are at risk of being infected with malaria. Despite the fact that the Bill and Melinda Gates Foundation has provided 100 million dollars to fund a malaria vaccination programme and scientists around the world are working hard to develop effective malaria vaccines, there is still no effective vaccine and medicine to provide reliable protection from infection and simultaneously promote long-term immunity.

Map of global malaria risk (2003) © WHO
Nevertheless, there is evidence that the immune system has found ways to protect humans against this tricky parasite. People who survive a malaria infection develop a growing resistance to the parasite. Adults often carry pathogens without revealing any disease symptoms. However, this “semi-immunity” only protects them in the region where they have grown up. In addition, they need to be repeatedly infected in order for the semi-immunity to be effective. While small children are the main victims of malaria, breast-fed babies hardly ever develop malaria. This is at least partially due to the antibodies taken up by the babies with their mother’s milk (see: Miksch G, Bannert B, Lucius R: “Parasiten: Überlebenskünstlern auf der Spur“, Kosmos, Stuttgart 2004).

“Natural needle-free vaccination"

No completely effective vaccine is yet available. A potential anti-malaria strategy might be to induce the human immune system to attack the parasites more effectively. A team of researchers led by Dr. Steffen Borrman from the Department of Infectiology (the former Hygiene Institute) at the University Hospital Heidelberg and Dr. Kai Matuschewski’s team from the Max Planck Institute for Infection Biology in Berlin (who previously worked in Heidelberg) may have discovered the first needle-free malaria vaccine in a mouse model (Science Translational Medicine, 14th July 2010).

Mice were administered an antibiotic for three days and were simultaneously infected with malaria. No parasites appeared in the blood and the animals treated in this manner also developed robust, long-term immunity against subsequent infections.

Sporozoite entering a liver cell. © Dr. Volker Brinkmann, MPI for Infection Biology, Berlin

Sporozoites were injected directly into the animals' blood. At the same time, the mice were treated with the antibiotics clindamycin or azithromycin. Normally, the sporozoites enter the liver where they replicate and mature into disease-causing blood stage forms (merozoites). The medication did not slow the maturing of the merozoites in the liver cells, but they prevented the erythrocytes in the blood from becoming infected. The typical disease symptoms caused by the disintegration of erythrocytes did not occur. The parasites that accumulated in the liver gave the immune system sufficient stimulus to develop robust, long-term immunity. After 40 days, four months and six months, the researchers again infected the mice with sporozoites, this time without adding antibiotics. All animals had complete protection against malaria.

When mimicking field conditions, where mosquito bites confront the human body with rather low, but frequent concentrations of parasites, the researchers found that 30 per cent of the mice were still protected. The malaria did not affect the brain in the animals that were infected, something that is of great clinical importance since it indicates a favourable prognosis.

Anopheles mosquito drinking human blood. © WHO

The findings of the researchers from Heidelberg and Berlin might open up strategies for new effective malaria prevention. "The antibiotics used in the experiments are affordable and do not cause undesired side effects. The prophylaxis with antibiotics in residents of areas with high malaria transmission has the potential to be used as a natural needle-free vaccination against malaria," said Borrmann. Matuschewski added: "The major motivation for our study was to test a simple concept that can also be used in malaria regions. We are convinced that weakened parasites offer the best protection against complex parasitical diseases such as malaria" (press release of the University Hospital Heidelberg, 15th July 2010).

A new target for malaria treatment

The antibiotics administered (clindamycin and azithromycin) target the apicoplast of the parasites, a small cellular organ of bacterial origin required by the parasites to penetrate other cells of the host organism. Since the medication blocking the apicoplast does not prevent the sporozoites from reproducing in the liver cell, the immune system is exposed to the full antigen load of a natural infection. This is not the case for previously developed vaccines with irradiated or genetically modified malaria pathogens. The apicoplast is characterised by a special lipid metabolism that does not occur in eukaryotic cells, which is most likely due to the fact that the apicoplast is the remainder of a red algal plastide (without photosynthesis) that was incorporated by a Plasmodium predecessor during evolution. Even if it is not possible to confirm the validity of a natural needle-free vaccination in a field trial as the researchers are hoping, the apicoplast is a promising target for future anti-malaria medication.

How malaria pathogens evade the human immune system

During evolution, malaria pathogens have developed many tricks for evading the attack of the human immune system. The life cycle of malaria parasites in the human body begins with an Anopheles mosquito that infects a person by drinking their blood. Infectious Plasmodium stages known as sporozoites enter the bloodstream, from where they leave again after only a few minutes. They go on to infect liver cells where they are relatively protected from attack by the body's immune system. The sporozoites multiply into merozoites which escape back into the bloodstream after around seven days. The merozoites then go on to infect red blood cells (erythrocytes) where they divide and reproduce. The erythrocytes burst and the newly released merozoites infect other erythrocytes within a few minutes. The erythrocytes burst synchronously, which increases the chance of some of the merozoites in the bloodstream avoiding the attack of the immune system. People respond to the destruction of erythrocytes with fever, with outbreaks occurring every 48 hours in those who are infected with P. falciparum. [Malaria often used to be referred to as remittent fever due to the regularity of fever attacks.] Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an infected person, it takes up gametocytes with the blood. The sporozoites travel to the mosquito's gut, where they sexually reproduce. New sporozoites develop and travel to the mosquito's salivary gland. The next time they drink human blood, they can potentially infect another person. The life cycle is complete.

Apart from the few short minutes they spend in the bloodstream (which is not long enough for the immune system to effectively attack them), the parasites hide in the liver and the blood cells where they are relatively invisible to immune surveillance.

Following their infection, the erythrocytes express adhesion proteins on their surface which causes them to get caught on the endothelium of the capillaries, thereby preventing them from travelling to the spleen where old and modified blood cells are normally destroyed. The pattern of the adhesion proteins determined by more than 100 Plasmodium genes constantly changes, thereby preventing the immune system from recognising the intruders. In addition, there are hundreds of Plasmodium strains in the tropics, each of them possessing slightly different surface protein patterns. This means that a vaccine that is able to protect against malaria in Tanzania, might be completely ineffective against West African malaria.

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