Most patients show some evidence of protective immunity against malaria. Often there is a period of tolerance after the primary attack, when there are no symptoms, but there are parasites in the blood. In addition, relapses are usually less severe than the primary attack. A resistance to superinfection occurs only as long as there is a low level of continued infection by the parasite. There is no cross immunity between P. vivax and P. falciparum. A lot of our knowledge about acquired immunity to malaria was initially obtained from observations of syphylitic patients undergoing "fever therapy" treatment by intentional infection with malaria.
The use of infection with malaria to treat syphillis began with the observation by Schaudinn that Treponema pallidum, the spirochete responsible for syphillis, was sensitive to temperatures a little above the normal body temperature of 98.6oC. Von Jauregg in 1917 inculated syphillitic patients with blood from patients infected with P. vivax. The syphilitic patients developed a 48 hr chill-fever cycle. After 3-4 cycles, he gave them quinine. The treatment proved to be very effective for late-stage syphillis; it stopped the progression of the disease although it did not cure it. Then, M. Ciuca tried using a newly discovered monkey malaria, P. knowlesi, instead of P. vivax. It actually worked as well as vivax, This therapy was used all over the world until the 1950's when antibiotics became available.
The type of protective immune response is probably cell-mediated. The parasite also induces a polyclonal B-cell activation. And there is also an immune suppression that occurs during the infection. Workers have speculated that the high frequency of Burkitt's lymphoma in regions of Africa endemic for malaria may be due to this immune suppression.
There are clear genetic differences in susceptibility to infection. One interesting example is the resistance of people heterozygous for the sickle cell anemia trait. This disease involves the change of a glutamic acid with a valine in hemoglobin which interferes with the conformation of hemoglobin and its ability to carry ozygen. The blood cells become "sickled" and get trapped in capillaries, causing organ damage, and they are more fragile and lead to anemia. Following is a figure of sickle-cells (taken from Stryer, Biochemistry, 4th ed., Freeman and Co., 1995):
This disease is fatal in the homozygous state. However, it is maintained in the population due to the positive selection of resistance to falciparum malaria.The "fitness" of people with the sickle-cell trait is 15% higher than that of a person with normal hemoglobin. In some regions of Africa, the frequency of this gene is as high as 40%. This represents an example of a "balanced polymorphism". This has led to the situation where in the United States, 10% of the African American population is heterozygous for this mutation. There are also several other undesirable genes which confer resistance to malaria in the heterozygote state and are therefore maintained in the population.
Following is a figure showing the correlation of the frequency of the sickle-cell trait with regions where malaria is prevalent (from Stryer, Biochemistry, 4th Ed., Freeman and Co., 1995):
The sickle-cell resistance phenomenon has been also examined in cultures of falciparum malaria. If heterozygous S/A red blood cells are used for the culture, the parasites can invade and become young rings, but they do not develop further and die. This provides an explanation of the protective effect of heterozygocity at the sickle-cell trait against infection with malaria.
Immunity to malaria is mainly due to the presence of cytotoxic T cells that act against the liver stages. T cells must be activated by antigen-presenting cells such as dendritic cells. Urban et al. (1999) showed that infected rbcs bind to dendritic cells and inhibit the maturation of these cells and thereby reduce their ability to stimulate T cells.
From Urban et al. (1999).
They suggested that the expression of parasite antigens at the surface of infected erthrocytes may have evolved to manipulate the immune system of the host. This is the third hypothesis for the role of the parasite surface antigens, but they may not be mutally exclusive.
Several human erythrocyte-related polymorphisms protect against malaria. In 1949 JBS Haldane hypothesized that b-thalassemia, caused by mutations in the b globin genes, and which result in a decrease or loss in hemoglobin production, may offer protection against malaria. Haldane’s malaria hypothesis is supported by the fact that the geographic distribution of the thalasssemias overlaps with that of endemic P. falciparum malaria, and populations with particular thalasssemias show less malaria. It has been proposed that the protection afforded by thalassemia may be due to a modification in surface receptors for P. falciparum, and in the case of P. vivax a-thalassemia may be associated with higher levels early in life thereby heightening immunologic defenses against subsequent attacks with the more dangerous P. falciparum.
Sickle cell trait
Sickle cell hemoglobin results from a change in a single amino acid in the beta chain of globin. When placed under reduced oxygen tensions red cells containing this hemoglobin change their form from a biconcave disc to become sickle-shaped. The gene is inherited autosomally and there is no dominance. The homozygous SS condition is responsible for the deadly effects of sickle-cell anemia, whereas the heterozygote with sickle cell trait is usually asymptomatic. The frequency of the sickle cell gene in parts of Africa can be as high as 40% whereas in the United States its frequency is less than 10%. In the 1950s AC Allison proposed that heterozygotes for sickle cell hemoglobin were protected against P. falciparum infections. Evidence has accumulated to show that the Hb S mutation has arisen on 4 separate occasions in Africa and the Middle East where falciparum malaria is endemic. Selection for AS carriers by malaria and selection against SS and AA individuals is an example of balanced polymorphism whereby an allele that is detrimental in the homozygous state is maintained due to a survival advantage of the heterozygote.
The manner whereby protection against P. falciparum is afforded by AS cells has been studied in vitro. If P. falciparum is grown in a flask in the lab and the O2 levels are lowered to 3% the parasites die. In the parasitized SS cell the sickle hemoglobin forms solid rods- it gels- and these rigid "spears" kill the parasite. In the parasitized AS cells some sickle but most just lose their intracellular water, and this suppresses parasite growth. Why 3% oxygen? Because that is probably the level of oxygen in the microvessels of the deep tissues.
Other predominant hemoglobin variants such as Hb E and HbC also have geographic distributions that suggest selection by malaria. Hb C results from a single amino acid substitution in the beta chain of hemoglobin and is common in West Africa. HbC, in both the heterozygous and homozygous state, is associated with a reduction in the risk of clinical malaria. Resistance may result from the poor growth of P. falciparum in such erythrocytes.
Glucose-6-phosphate dehydrogense deficiency
Glucose-6-phosphate dehydrogenase deficiency, or favism, is a syndrome that results in decreased activity in the hexose monophosphate shunt, which generates reducing power and protects the red cell from oxidant stress. Its distribution is also correlated with malaria endemicity in Africa, Asia, the Middle East and the Mediterranean. The manner of protection is still unclear but studies suggest that infected red cells may be more susceptible to phagocytosis or hemolysis due to damage inflicted by parasite-produced oxidants.
P. vivax merozoites require the Duffy chemokine receptor for invasion. A large fraction of the African population especially in West Africa is Duffy negative meaning they lack the Duffy factor on their red cells; such individuals are refractory to vivax malaria. Similarly, individuals who are genetically deficient in red cell glycophorin A (Ssu or Ena-) are incapable of being invaded by falciparum merozoites.
Changes in the erythrocyte membrane anion exchanger, band 3 protein, produce a syndrome known as Southeast Asian ovalocytosis; these abnormally shaped oval red cells have a decreased deformability and may resist infection because the red cell membrane cannot be invaginated during merozoite invasion
Immune system polymorphisms have been documented for several infectious diseases including malaria. For example, epidemiological studies in West African populations have shown an association of the human leukocyte antigen (HLA-B53) with resistance to severe malaria.