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Cell biology

Scenes of a parasite

Brazilian biophysician discovers in Paris how the malaria protozoon spreads through the body

ROGERIO AMINO/UNIFESPLike a corkscrew: Plasmodium perforates the skin of ratsROGERIO AMINO/UNIFESP

In its voracious search for blood, the female of the Anopheles mosquito can cause more than pain and itching. It often leaves in the body of its victims a few dozen specimens of the parasite that causes malaria, one of the most common infectious diseases in the world, which every year affects about 300 million persons and causes the death of 1 million.  Long known to humanity – Hippocrates, the Greek, regarded as the father of medicine, described it some 2,500 years ago -, malaria began to be better understood at the end of the 19th century, when the French surgeon Charles Louis Alphonse Laveran identified the microorganism that caused it, protozoa from the Plasmodium genus.

Over one century after the discovery that contributed towards Laveran being given the Nobel in Physiology in 1907, experiments done at the Pasteur Institute, in Paris, by Brazilian biophysician Rogerio Amino and by German parasitologist Friedrich Frischknecht reveal details about the behavior of this parasite that can re-steer the development of vaccines against malaria.

Invited by Frischknecht to do a two years postdoctoral job at the Pasteur’s Malaria Biology and Genetics Unit, headed up by Robert Ménard, Amino decided to see how the Plasmodium infects live organisms. Since the times of Laveran it is known that the parasite is injected into the body of mammals at the moment the insect bites, but no one had observed the protozoon’s route to the cells of the liver, where it lodges and multiplies rapidly before occupying the red cells of the blood.

Amino and the German parasitologist contaminated specimens of the Anopheles stephensi mosquito, responsible for the transmission of human malaria in Asia, with the Plasmodium berghei protozoon, genetically altered to produce a fluorescent green protein. Next, they let the insects bite the ears of anesthetized rats and mice. With the assistance of a confocal laser microscope, which makes it possible to observe structures under the skin of living beings and to reconstruct the images in three dimensions, they followed step by step what was happening.

Right at the outset, novelties arose. In the bite, the insect does not inject the specimens of the protozoon into the inside of the blood vessels, as it used to be supposed. The greater part of the mosquitoes throws 10 to 20 parasites mixed with saliva into a deeper layer of the skin – at 50 thousandths of a millimeter from the surface, close to the region where hairs are born. “This result confirmed an old suspicion”, says Amino, a professor at the Federal University of São Paulo (Unifesp).

Before investigating malaria, Amino was studying the transmission of another protozoon – the Trypanosoma cruzi, which causes Chagas’s disease, transmitted by the kissing bug – and he knew that the insect’s saliva was inoculated into the skin, and not directly into the blood vessels. As it contains pharmacologically active compounds, the saliva of the kissing bug could facilitate the insect’s access to the blood. If it was like that with the kissing bug, Amino imagined that the same could occur with the Anopheles.

The most important thing, though, happened next. Seven hours after the mosquito feeding on the rodents’ ears, there were still protozoa at the spot of the bite, according to a study published on January 22 in the online edition of Nature Medicine. Half of the parasites practically does not move and dies at the spot where they were deposited. The rest can take two courses, with very different destinations. Seven out of every ten specimens of the Plasmodium moves using movements that are reminiscent of a corkscrew, perforating the cells they find in their way, at a speed of 1 micrometer per second. It does not seem much, but it is sufficient for them to reach the bloodstream a few minutes after the bite.

Between life and death
Once in the blood, each parasite – which until then was in the sporozoan stage, with an elongated format like a banana – can invade the liver, where it starts reproducing rapidly, generating 30 thousand copies of the protozoon. Now with the format of a pear, called merozoite, the parasite leaves the liver and goes back to the blood, where it infects the red cells. It is the start of another stage of multiplication. Which ends with the explosion of the blood cells and fevers of up to 40°C, capable of leaving anybody in bed, with their teeth chattering and anemia.

The other copies of the Plasmodium that escape from the place of the bite follow a suicidal route never imagined: they cross through the cells of the skin until they hit the lymphatic vessels, channels close to the blood vessels that, instead of blood, transport lymph, a whitish liquid rich in fats, proteins and the organism’s defense cells. Led by the lymph to the lymph nodes, small ganglia with a large concentration of defense cells called lymphocytes, these protozoa find their final destination. The greater part is destroyed in up to four hours.

A few specimens survive for up to 24 hours and mature, taking on the form corresponding to the one they acquire in the liver, before dying. “This discovery is important, because it is in the lymphatic system that the organism’s immune response is produced”, says Amino. “Whenever you advance in biology, an application arises sooner or later”, comment Victor and Ruth Nussenzweig, a couple of Brazilian researchers who are working on the development of a vaccine against malaria in New York University, United States.