PEN BY: Binod Rayamajhee; Malaria is a disease caused by a protozoan, a member of the sporozoa group. The malaria parasite is one of the most important human pathogens and has played an important role in the development and spread of human culture. As we will see, malaria has even affected human genetics and evolution. Malaria is still a significant human disease even though there are several effective treatments available. Over 100 million people worldwide have malaria, and each year over 1 million of these will die. The mammalian reservoir for malaria is humans. Four species of sporozoa infect humans. The most wide spread is Plasmodium vivax and the most serious is Plasmodium falciparum. The parasite carries out part of its life cycle in human reservoir and part in the mosquito vector, which spreads the parasite from person to person. Only female mosquitoes of the genus Anopheles transmit malaria.
Anopheles mosquitoes inhabit warmer parts of the world; therefore, malaria occurs predominantly in the tropics and subtropics, malaria did not exist in the northern regions of North America prior to settlement by Europeans but was a major problem in area such as the Southern United States, where appropriate mosquito habitat existed. The disease is associated with wet low lying areas, and the name malaria is derived from the Italian words for “bad air”.
The life cycle of the malaria parasite is complex. First, the human host is infected by plasmodial sporozoites, small, elongated cells produced in the mosquito, which localize in the salivary gland of the insect. The mosquito injects saliva (containing an anticoagulant) along with the sporozoites. The sporozoites travels through the blood streams to the liver, where they may remain quiescent, or they may replicate and become enlarged in a stage known as a schizont. The schizonts then segment into a number of small cells called merozoites, and these cells are liberated from the liver into the blood stream. Some of the merozoites then infect red blood cells (erythrocytes). The cycle in erythrocytes proceeds as in the liver and, in the case of P. vivax, usually repeats at synchronized intervals of 48 hours. During this 48-hour period, the defining clinical symptoms of malaria occur, characterized by chills followed by fever of up to 40C (104F). The chill-fever pattern occurs with the release of P. vivax cells from the erythrocytes during the synchronized asexual reproduction cycle. Vomiting and severe headache may accompany the chill fever cycles, and asymptomatic periods generally alternate with periods in which the characteristics symptoms are present. Because of the loss of red blood cells, malaria generally causes anemia and some enlargement of the spleen.
Not all protozoal cells liberated from the red blood cells are able to infect other erythrocytes. The protozoal cells that cannot infect other erythrocytes are called gametocytes are infective only for the mosquito. These gametocytes are ingested when another Anopheles mosquito bites the infected person; they mature within the mosquito into gametes. Two gametes fuse, and a zygote is formed. The zygote then migrates by amoeboid motility to the other wall of the insect’s intestine where it enlarges and forms a number of sporozoites. These are released and some reach the salivary gland of the mosquito, from where they can be inoculated into another human, and the cycle begins again.
Diagnosis and Treatment:
Conclusive diagnosis of malaria in humans requires the identification of Plasmodium infected erythrocytes in blood smears. Fluorescent nucleic acid stains, nucleic acid probes, polymerase chain reaction (PCR) methods, and antigen-detection methods may all be used to verify Plasmodium infections, or to differentiate between infections with various Plasmodium species.
Prophylaxis (when travelling to endemic areas) and treatment of malaria are usually accomplished with Chloroquine. Chloroquine is the drug of choice for treating parasites within red cells, but does not kill malarial parasites outside the cells. The closely related drug primaquine eliminates sporozoites, merozoites and gametes outside the cells. Treatment with both Chloroquine and Primaquine produces a cure. However, even in individuals who have undergone drug treatment, malaria may recur years after the primary infection. Apparently, small numbers of sporozoites survive in the liver and can reinitiate malaria months or years later by releasing merozoites.
In many parts of the world Plasmodium strains have developed resistance to Chloroquine or Primaquine or both, and some strains have developed resistance to other drugs as well. For use in areas with known drug-resistant strains, Mefloquin or Doxycycline is prescribed for prophylaxis and Malarone, a combination of Atovaquone and Proguanil, is recommended for both treatment and prophylaxis. A new category of anti-malarial drugs are synthetic derivatives of Artemisinin, a natural compound containing reactive peroxide groups that form free radicals. These compounds are anti-parasitic agents in vivo and are now undergoing clinical trials.
Anti-malarial drug treatment is an expensive and short term solution to malaria prevention and control, and drug resistant strains of the parasite complicate matters even further. The most effective control measure is to interrupt the life cycle of the parasite by eliminating one of the obligate hosts, the Anopheles mosquito.
Two approaches to mosquito control are possible:
1. Elimination of habitat by drainage of swamps and similar breeding areas, or
2. Elimination of the mosquito by insecticides, followed by treatment of patients with primaquine, thereby breaking the Plamodium life cycle.
The overall public health treatment from malaria in the United States in now minimal, very low number of endemic malaria cases have resurfaced in recent years as far north as New York City. Significant periodic increases in malaria incidence also occur due to causes imported by soldiers or immigrants from malaria endemic areas. On average, about 1,500 cases of malaria and five deaths occurs in the United States each year.
In other parts of the world, eradication has been much slower, but the same control measures are used and are still effective. Reduction, of mosquito habitat, control of mosquitoes by insecticides, and treatment of infected individuals with drugs both for cure and prophylaxis are still the major strategies for controlling malaria. Several malaria vaccines are in development, including synthetic peptide vaccines, recombinant particle vaccines, and DNA vaccines.
Malaria and Human Evolution: –
Malaria has undoubtedly been endemic in Africa for thousands of years. In West Africans, resistance to malaria caused by Plasmodium falciparum is associated with an altered red blood cell protein, hemoglobin S, which differs from normal hemoglobin A at only a single amino acid valine is substituted for the glutamic acid of hemoglobin A. As a result, hemoglobin S binds oxygen less efficiently than hemoglobin A under conditions of low oxygen concentration, hemoglobin S forms long, thin aggregates that cause the red cell to change from a biconcave round cell to an elongated C-shaped cell. Because of the shape of the cell, this condition is known as a sickle cell. Individuals who are homozygous for the sickle cell trait are particularly susceptible to changes in oxygen concentrations and suffer from Sickle Cell anemia.
Individuals who are heterozygous for hemoglobin S have the sickle cell trait, but have increased resistance to malaria. With the sickle cell hemoglobin S can still produce sickled cells but not as readily as in the case of the homozygote. However, the growth of P. falciparum inside the red cell causes the heterozygous cells to sickle more easily than uninfected cells. The aggregated hemoglobin S in sickled cells apparently disrupts the membrane of red cells, allowing potassium to diffuse from the cell. P. falciparum cannot grow in the low potassium environment of the disrupted cell. Thus, persons with the sickle cell trait are resistant to malaria.
In certain Mediterranean regions where malaria is endemic, resistance to Plasmodium falciparum is associated with a deficiency in the red blood cells of the enzyme glucose-6-phosphate dehydrogenase (G6PD), an enzyme that acts as an intracellular antioxidant (reducing) compound. The faulty G6PD leads to higher levels of intracellular oxidants such as the H2o2 produced inside the red cell by the growing Plasmodium falciparum. The increased levels of oxidants, normally removed by the activity of functional G6PD, damage parasite membranes and limit parasite growth.
In many Mediterranean populations, a diverse group of genetic abnormalities affects hemoglobin production and efficiency. These are known collectively as the thalassemias. The thalassemias are also statistically and geographically associated with increased resistance to malaria, and like the G6PD deficiency, are associated with decreased levels of antioxidants in red cells.
Hemoglobin S, G6PD deficiency and thalassemias are the result of genetic mutations that confer resistance to malaria infections and thus are selected in the population, although the mutations also confer red blood cell abnormalities and oxygen-processing deficiencies.
Another case in which the malaria parasite influences evolution involves the major histocompatibility complex (MHC) and the immune system. As mentioned above, the MHC class I and class II proteins present antigens to T cells for initiation of an immune response. In malaria prone equatorial West Africa, individuals are very likely to have one particular MHC class I gene and one particular set of class II genes. These selected MHC genes are more common in the West African population and are virtually unknown in other human population groups. Individuals who express these genes have as much resistance to severe fatal malaria infections as those with the hemoglobin S trait. The MHC proteins encoded by these selected genes are exceptionally good antigen presenting molecules for certain malarial antigens and initiate a strong protective immune response to Plasmodium spp infection. As is the case for selection of the hemoglobin variants, the parasite is a selection factors for MHC genes that enhance host survival. Individuals with selected MHC genes that confer malaria resistance have a measurable survival advantage and are more likely to live and pass the resistance conferring genes to their descendent.
Thus, in several ways malaria has been a selective agent in human evolution. Other pathogens such as Mycobacterium tuberculosis and Yersinia pestis, may also have promoted selective changes in humans, but in no case is the evidence as clear as it is for malaria.
Mr. Rayamajhee has gained the degree of M. Sc. In Medical Microbiology.
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