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Malaria

Malaria is one of the most deadly diseases on earth (Africa, Asia, and South America), killing 1-2 million people per year and exhausting the life of many more people. Children and pregnant women are the most vulnerable groups to malaria. The economic burden of the disease is very important in sub-Saharan Africa

Malaria is a disease transmitted through infected female Anopheles mosquitoes during the blood meal. The male Anopheles does not feed on blood. Female feed most often at night. Humans as well as mosquitoes are utilised by the parasite that is the cause of malaria. In humans, the parasite multiplies first in the liver, then spread to the blood where it invades the red blood cells, our system for oxygen transport from the lungs to the rest of the body. A single invading parasite may have billion of descendants within some weeks. Mosquitoes pick up the parasites from our blood and they mate and proliferate in the mosquitoes. Mating means the same for the parasite as for other living organisms: a recombination of inherited abilities. Therefore, each new bite of an infected mosquito can deliver parasites with new infectious abilities potentially overcoming immunity and vaccines.

Why do we become sick?

When the parasite is in the liver, the individual has no symptom of the disease. Usually symptoms of malaria caused by the P.falciparum parasite appear 6-14 days following infection. The infection of the red blood cells is the starting point for the erythrocytic stage of the life cycle of the parasite. The parasite utilises the proteins in these cells for its own multiplication. This process takes 3-4 days and is synchronised for all descendants of the originally invading parasite. When the parasites are mature enough inside the red blood cells, there is a rupture of the red blood cells, and the parasites are in the blood stream and occasionally invade new red blood cells.

The presence of free parasites in the blood stream induces the apparition of the symptoms of malaria infection: fever, anaemia, vomiting, shivering and sometimes convulsions. Most of the time, symptoms begin with coldness following by rigor and fever for 4-6 hours. Once the rests of the burst blood cells are removed from the blood and the parasites have invaded new blood cells, the fever descend. This is the well known cycles of fever that characterize malaria.

When the parasite invades the red blood cells, they modify these cells in many ways. One is that the surface of the red blod cells change and they become sticky and may adhere to the cells of the small blood vessels. Doing that, they may stop the blood flow. If this occurs in the brain, a severe form of malaria is a result: the human, often a small child, goes into shock with spasms and high fever and left untreated, will often die.

If the malaria is not treated or the human immune system wins over the malaria, this process will gradually lead to coma and death especially in children and pregnant women where the immune system is not fully developed or temporarily reduced, respectively. The severity of malaria symptoms are anaemia, hyperparasitemia, and damage can occur in the brain, spleen, liver and kidneys. In pregnant woman, the parasite can also attack the placenta thus reducing the oxygen and nutritional transfer leading to reduced weight of the newborn and putting as well the mother as the child life at increased risk.

Immune reactions and vaccines

The malaria parasite has lived with humans for thousands, perhaps million of years. It has thus developed mechanism to avoid to be killed by our normally very effective immune system. Our immune system works in the way that it recognises some molecules on the surface of invading bacteria, virus or parasites. Once recognised, the immune system has several ways of killing the invader. To avoid being killed, the malaria parasite has developed an effective weapon: the variation of proteins presented at its cell surface and on the surface of the infected red blood cell. Using this strategy, all the malaria parasites are more or less different and a single parasite is also able to vary during the course of an infection. So, once our immune system has developed a defence against one type of malaria parasite, after sometime the parasite is no longer recognised. This is a potentially deadly competition between the parasite and our body. If in the end, our immune system recognises various forms of the parasite, human host survives and at next infected mosquito bite, he/she has a better defence than before. If not, human host dies. The more the individual has malaria infection, the better the immune system develops appropriate responses against the malaria parasite. This takes time, about 5 years for developing the immunity against the disease and about 12-15 years for developing anti-parasite immunity for people living in high malaria endemic countries. This is why small children are especially sensitive.
But, our immune system forgets. This is why after a year or two outside a malaria area, people coming back get sick as small children. In areas where adults are not exposed to malaria every year, the disease spreads as an epidemic, the immune experience is gone.
Vaccine developers are trying to identify parasite molecules on the surface of the infected red blood cells that are stable (do not change between the different type of malaria parasites). These exist, but they are also more hidden for our immune system. Still, the parasite also change each time they mate in mosquitoes and it is not yet known if any of the now promising vaccine candidates will be effective for longer time.

Medicine

Chloroquine was for long time and effective and cheap medicament, but in many countries, it is no longer effective. Genetic changes in the parasites overcame the efficacy: the parasite became resistant to chloroquine. This has been repeated for many other malaria drugs in the last years, and the newer drugs that are still effective, are more expensive. One group among these is based on a plant extract from Artemisia annua, a family of weed plants found in many countries. This plant was used in traditional Chinese medicine against malaria, and when most synthetic made medicine failed, the pharmaceutical industry started working with these plant extracts. The active molecule is extracted and isolated, it may be chemically modified to be more stable and effective and it is sold combined with a synthetic drug. This is to avoid that the parasite becomes resistant to this drug also. Artemisia can be grown in many tropical countries the point is also to have good extraction facilities. Quinine is actually used for the treatment of severe malaria. The World Health Organization recommended the use of combination therapies for the treatment of uncomplicated malaria and intermittent preventive treatment for pregnant women. Sulfadoxine-pyrimethamine (SP) is the antimalarial medicine recommended for the prevention of malaria during pregnancy. WHO recommends at least 2 doses of SP during regularly scheduled antenatal visits after the first trimester.

Mosquito control

Without mosquitoes, no spread of malaria (and these mosquitoes could say the same for humans). Human malaria is only spread by species of the mosquito called Anopheles. As larvae they are easily recognised in water, they do not move like small worms or snakes like the other mosquito larvae, but swim as their body is stiffer. The adults can be recognised by the way they sit with the hind legs in the air and the brushy antenna on the head. When flying, they make very little noise compared to the other mosquitoes that attack us. Anopheles species live in different ways in different countries. In Africa, the most important species breed as larvae in sun exposed water and the adults rest in our houses and bite also indoor. In Asia and Latin America, many species live in the forests, breed in shadowed water and bite outdoor only, but other species have a life more like the species in Africa. Mosquito control therefore cannot be the same all over the world.

Preventing is always the best approach. Malaria control was obtained in Europe and US by drying out mosquito breeding sites and use screens to prevent the mosquitoes to enter houses and bite people. Chemical control only played a minor role. These methods are effective where mosquito breeding sites are well defined and where the society is well organised and can afford and use the screening correctly.

Where mosquitoes rest and bite indoor, spraying of houses can be effective, but opposite to the prevention described above, mosquitoes like parasites can develop resistance. DDT was used on large scale in Asia, Latin America and Africa, but caused high resistance in Asia and parts of Africa that made this control form obsolete. When the spraying changed to other insecticides that were more toxic to humans and often badly smelling, these campaigns became very unpopular and was abonded. To-day, pyrethroids like Permethrin, Deltamethrin, Lamdacyhalothrin etc are often used, they are low toxic to humans, very toxic to mosquitoes and do not stink. They are also used in agriculture, and in some areas of West Africa, the spread of these insecticides in irrigated cultures expose the mosquito larvae and caused resistance that is transferred to the adult mosquitoes also. This resistance also works against DDT.

Bed-nets have been used for thousand of years; it is told that rich people in the old Egypt used these. As long as they are intact and no human skin is in contact with the net, mosquitoes cannot reach to bite. Unfortunately, bed-nets easily gets holed and people often have a leg or arm in contact with the net and get bitten through the net. Dipping such nets in insecticide solutions was a big progress invented in the 80ies. The bed-nets now became mosquito traps, the humans sleeping under the net became the bait, and the mosquito walking on the net trying to get in, became prey and killed. But nets become dirty and needs washing, and then the insecticide is washed off again. This problem was overcome by factory impregnating the nets and either having the insecticide inside the net yarn (Olyset, Netprotect, Icon Life) or in a coating layer on the yarn (Permanet,   ). New nets are developed and marketed continuously; so far all contains pyrethroids and are thus potentially rendered less effective if the resistance to this group of insecticide develops on a larger scale.

Larvicides can be used to kill the mosquito larvae. Synthetic insecticides may work, but there are also several products based on bacteria that only kills mosquito larvae and thus are not dangerous for fish if such are found near or in the same water or for animals that may drink the water. Where breeding sites are easily recognised as in urban and peri-urban areas, mosquito larvae control is an easy and cheap control form. The problem is that it only works when done co-ordinated and on a larger scale. There is limited advantage of controlling the breeding site at your house if the neighbours do not the same, but if most people in an area control the larvae, there will be very few adult to bite. The adult mosquitoes do not fly very far, preferring to bite those living close to the place where they lay their eggs.  
 

By Francine Ntoumi and Ole Skovmand

 
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