Malaria (Italian: "bad air"; formerly called ague or marsh fever in English) is an infectious disease which in humans causes about 350-500 million infections and approximately 1.3 million deaths annually, mainly in the tropics. Sub-Saharan Africa accounts for 85% of these fatalities.
Malaria is caused by the protozoan parasite, Plasmodium (one of the Apicomplexa) and the transmission vector for human malarial parasite is the Anopheles mosquito. The P. falciparum variety of the parasite accounts for 80% of cases and 90% of deaths. Pregnant women and infants under the age of five are most vulnerable to malaria.
Mechanism of the disease
Infected female Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. If they bite a person, which they usually do starting at dusk and continuing throughout the night, the sporozoites enter the person's body via the mosquito's saliva, migrate to the liver where they multiply within hepatic liver cells. There they develop into merozoites which then enter red blood cells, where they multiply further, periodically breaking out of the red blood cells. The classical description of waves of fever coming every two or three days arises from simultaneous waves of merozoites breaking out of red blood cells during the same day.
The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it stays inside liver and blood cells. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the parasite produces certain surface proteins which infected blood cells present on their cell surface, causing the blood cells to stick to the walls of blood vessels. These surface proteins known as PfEMP1 are highly variable (there are at least 50 variations) and cannot serve as a reliable target for the immune system.
By the time the human immune system learns to recognise the protein and starts making antibodies against it, the parasite has switched to another form of the protein, making it difficult for the immune system to keep up.
The stickiness of the red blood cells is particularly pronounced in Plasmodium falciparum malaria and this is the main factor giving rise to hemorrhagic complications of malaria.
Some merozoites turn into male and female gametocytes. If a mosquito bites the infected person and picks up gametocytes with the blood, fertilization occurs in the mosquito's gut, new sporozoites develop and travel to the mosquito's salivary gland, completing the cycle.
Pregnant women are especially attractive to the mosquitoes, and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight.
The recognised species causing disease in humans are P. falciparum (which alone accounts for 80% of the recognised cases and ~90% of the deaths), P. vivax, P. ovale, and P. malariae. Infections with P. knowlesi and P. semiovale are also known to cause malaria but are of limited major public health importance.
High endothelial venules (the smallest branches of the circulatory system) can be occluded by the infected red blood cells, such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells affect the integrity of the blood brain barrier possibly leading to reversible coma. Even when treated, serious neurological consequences may result from cerebral malaria, especially in children.
Other mammals (bats, rodents, non-human primates) as well as birds and reptiles also suffer from malaria. However, the form of malaria found in animals is usually different than that found in humans. Three human forms (which account for most malaria cases) are completely exclusive to humans. Only one form, P. malariae, can cause malaria in both humans and higher primates. Other animal forms of malaria do not infect humans at all. Mosquitos which are "virgin" (i.e. have never bitten someone before) cannot transmit malaria, even if the eggs were laid by a female carrier of the disease.
Sickle cell anemia and other genetic effects
Carriers of the sickle cell anemia gene are protected against malaria because of their particular hemoglobin mutation; this explains why sickle cell anemia is particularly common among people of African origin. They have a specific variant of the beta-globin gene. Some scientists hypothesize that another hemoglobin mutation, which causes the genetic disease thalassemia, may also give its carriers an enhanced immunity to malaria.
Another disease which is linked to protection against malaria is glucose-6-phosphate dehydrogenase deficiency (G6PD). It protects against malaria caused by Plasmodium falciparum as the presence of this enzyme is critical to survival of these parasites within red blood cells.
It is thought that humans have been affected by malaria for about 50,000 years, and several human genes responsible for blood cell proteins and the immune system have been shaped by the struggle against the parasite.