Plasmodium Genome

There are at least two benefits to decoding the parasite's genome. One is to find a protein or biochemical reaction that is unique to Plasmodium species such that a drug can be designed that is selectively toxic to the protozoan. A second goal is to understand the genetic changes that lead to drug resistance. One of the main reasons for the increase in malaria since the late 1990s is the developing resistance to chloroquine, an antimalarial that has been widely used against P. falciparum. This resistance is blamed for the increasing mortality rates in Africa and to the resurgence of malaria.

The P. falciparum genome consists of the 30 million base pairs, forming 5,000 to 6,000 genes. It is nearly 80% adenine (A)-thymine (T) rich, making it difficult to tally base pairs on the parasites' 14 chromosomes.9,10 (In contrast, the human genome is about 59% A-T.) The high A-T concentration made determination of the Plasmodium genome difficult to sequence because (a) it was more difficult to slice the chromosomal deoxyribonucleic acid (DNA) strands into smaller distinct segments that make it easier to sequence the nucleotides and then reassemble them into chromosome; and (b) the computer software would fail and had to be mod-ified.11 Because P. vivax is difficult to propagate in the laboratory, obtaining its genome has been a challenge. It turns out that although it resembles P. falciparum's genome, it possesses novel gene families and potential alternative invasion pathways not previously recognized.12

Human Mutations that Protect against Malaria

There are at least six mutations in the human species that provide protection against malaria. These predominate in populations that historically lived and continue to live in areas endemic with malaria. The six mutations are sickling disease (formerly sickle cell anemia), glucose-6-phosphate dehydrogenase deficiency, hemoglobin C, various thal-assemias, increased production of nitric oxide (NO), and pyruvate kinase deficiency. Sickling disease can be fatal in homozygotes although treatment has greatly improved. Heterozygotes usually are asymptomatic and show a 90% decrease in the chance of dying from P. falciparum.13 Homozygotes with hemoglobin C usually are asymptom-atic.14 Erythrocyte glucose-6-phosphate dehydrogenase deficiency (actually 10%—15% of normal activity in the erythrocyte) can cause hemolytic anemia and prehepatic jaundice when the patient takes certain drugs or is exposed to some viral infections. Ironically, some of the antimalarial drugs must be used with caution in patients with erythrocyte glucose-6-phosphate dehydrogenase deficiency to minimize the risk of hemolytic anemia. The increased levels of oxidized glutathione in the erythrocyte that are deficient in this enzyme may prevent the parasite from maturing in the erythrocyte. The significance of thalassemia varies with the type of anemia and whether or not the patient is homozygote or heterozygote. The most recent identified mutation is pyruvate kinase deficiency. Because erythrocytes lack mitochondria, this enzyme is key to the formation of adenosine triphosphate (ATP) from phosphoenolpyruvate.15 These mutations produce an erythrocyte such that the parasite has difficulty reproducing.

Another mutation is the ability of certain populations to increase their production of NO. The site is in the promoter region of the gene for nitric oxide synthase 2 that generates NO from arginine and involves a mutation where cytosine is replaced by thymine. The result is higher circulating levels of NO. Mechanistically, it is not known how increased NO provides this protection, because there appears to be no significant difference between blood levels of the parasite in individuals with the mutation compared with those with "normal" NO synthase. The protection may be from complications seen with malaria, giving the patient's immune system time to respond to the parasite.16

Controlling the Vector, the Anopheles Mosquito

The Anopheles mosquito has adapted very well to human habitats. As already pointed out, it requires still water to lay its eggs, wait for them to hatch, and then let the larvae, who feed on microscopic organisms in the still water, mature. Transient still water is ideal because it likely is not going to contain predators that will feed on the eggs and larvae. In general, mosquitoes need 1 to 2 weeks to develop into mature insects. This usually is enough time before predators begin to populate the still water.

Currently, there are two ways to control the mosquito carrier. One is to prevent contact between humans and the insect. Because the Anopheles mosquito is a nocturnal feeder, it is easier to control compared with the Aedes aegypti mosquito, which is a day feeder and carries both dengue and yellow fever. Putting screens on windows and using mosquito netting in bedrooms are very effective. The latter, when insecticide impregnated, has proven very effec-tive.17 As simple as the use of treated nets may seem, they produce a logistical challenge. It has been estimated that in 2007, 130 to 264 million treated nets are required to reach 80% coverage for 133 million children younger than 5 years and pregnant women living in 123 million households in risk areas in Africa.18

Second, elimination of the Anopheles mosquito, usually by application of insecticide and destroying its breeding areas, are the most effective ways to eliminate (as opposed to control) malaria. Areas that have been successful at eliminating infected mosquitoes include North America, Europe, and Russia. To do this, the adult female mosquito must be killed and breeding areas (still water) must be drained. One of the most effective insecticides has been dichlorodiphenyl-trichloroethane (DDT). Dr. Paul Muller received the 1948 Nobel Prize in Medicine for discovering that DDT kills the malaria-carrying Anopheles mosquito. DDT is very long lasting and, unfortunately, accumulates in the environment. Although being long lasting is beneficial from the standpoint of mosquito control, it also means that these insecticides get into the food chain and can affect both animals, including birds, and humans. Indeed, use of DDT has been banned in most economically developed countries. Unfortunately, the areas of the world where malaria is endemic are economically poor and cannot (a) afford the newer insecticides that must be reapplied because they degrade, (b) fund and maintain the infrastructure to eliminate breeding areas, and (c) provide medical facilities, staff, and drugs to treat their citizens.

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