Plasmodium falciparum

Plasmodium falciparum
Scientific classification
Kingdom:	Protista
Phylum:	Apicomplexa
Class:	Aconoidasida
Order:	Haemosporida
Family:	Plasmodiidae
Genus:	Plasmodium
Species:	P. falciparum
Binomial name
	Plasmodium falciparum; Welch, 1897

Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by Anopheles mosquitoes. P. falciparum is the most dangerous of these infections as P. falciparum malaria has the highest rates of complications and mortality. In addition it accounts for 80% of all human malarial infections and 90% of the deaths. It is more prevalent in sub-Saharan Africa than in other regions of the world.

Background

Malaria is caused by infection with protozoa of the genus Plasmodium. The name malaria, meaning bad air, comes from the linkage suggested by Lancisi (1717) of malaria with the poisonous vapours of swamps. The organism itself was first seen by Laveran on November 6th 1880 at a military hospital in Constantine, Algeria, when he discovered a microgametocyte exflagellating. Manson (1894) hypothesised that mosquitoes could transmit malaria - an association made considerably earlier in India, possibly as early as 2000BC. This hypothesis was experimentally confirmed independently by Giovanni Battista Grassi and Ronald Ross in 1898. Grassi (1900) proposed an exerythrocytic stage in the life cycle and this was later confirmed by Short, Garnham, Covell and Shute (1948) who found Plasmodium vivax in the human liver.

Malaria has been a scourge throughout history and has killed more people than all wars and other plagues combined. It remains globally the most important parasitic disease of man and claims the lives of more children worldwide than any other infectious disease. Since 1900 the area of the world exposed to malaria has been halved but in this time two billion more are presently exposed. Morbidity as well as mortality is substantial. Infection rates in children in endemic areas are of the order of 50%: chronic infection has been shown to reduce school scores by up to 15%. Reduction in the incidence of malaria coincides with increased economic output.

While there are no effective vaccines for any of the six or more species that cause human malaria, drugs have been employed for centuries. In 1640 Huan del Vego first employed the tincture of the cinchona bark for treating malaria: the native Indians of Peru and Ecuador had been using it even earlier for treating fevers. Thompson (1650) introduced this "Jesuits' bark" to England: its first recorded use there was by Dr John Metford of Northampton in 1656. Morton (1696) presented the first detailed description of the clinical picture of malaria and of its treatment with cinchona. Gize (1816) studied the extraction of crystalline quinine from the cinchona bark and Pelletier and Caventou (1820) in France extracted pure quinine alkaloids which they named quinine and cinchonine.

Attempts to make synthetic antimalarials began in 1891. Atebrin was developed in 1928, was used widely throughout the Pacific in World War II but was deeply unpopular because of the yellowing of the skin it caused. The Germans developed chloroquine in the late 1930s which went into use in the North African campaigns. Mao Tse-tung encouraged Chinese scientists to find new antimalarials after seeing the casualties in the Vietnam War. Artemisinin was discovered in the 1970s based on a medicine described in China in the year 340. This new drug became known to Western scientists in the late 1980s and early 1990s and is now a standard treatment.

Resistance to antimalarial drugs, first to chloroquine and then to others was first noticed in the 1950s and has since spread all over the world.

Although an antimalarial vaccine is urgently needed, infected individuals never develop a sterilizing (complete) immunity, making the prospects for such a vaccine dim. The parasites live inside cells, where they are largely hidden from the immune response. Infection has a profound effect on the immune system including immune suppression. Dendritic cells suffer a maturation defect following interaction with infected erythrocytes and become unable to induce protective liver-stage immunity. Infected erythrocytes directly adhere to and activate peripheral blood B cells from nonimmune donors. The var gene products, a group of highly expressed surface antigens, bind the Fab and Fc fragments of human immunoglobulins in a fashion similar to protein A to Staphlococcus aureus and this may offer some protection to the parasite from the human immune system. Despite the poor prospects for a fully protective vaccine, it may be possible to develop a vaccine that would reduce the severity of malaria for children living in endemic areas.

Microscopic appearance

Among medical professionals, the preferred method to diagnose malaria and determine which species of Plasmodium is causing the infection is by examination of a blood film microscopically in a laboratory. Each species has distinctive physical characteristics that are apparent under a microscope. In P. falciparum, only early trophozoites and gametocytes are seen in the peripheral blood. It is unusual to see mature trophozoites or schizonts in peripheral blood smears as these are usually sequestered in the tissues. The parasitised erythrocytes are not enlarged and it is common to see cells with more than one parasite within them (multiply parasitised erythrocytes). Occasionally, faint comma-shaped red dots are seen on the red cell surface called "Maurer's dots".

Plasmodium and the human genome

In the 50,000 years since Plasmodium first infected humans, these parasites have altered the human genome in a multitude of ways. Haldane (1949) suggested that Sickle-cell disease could offer some protection to malaria. This hypothesis has since been confirmed and has been extended to hemoglobin C and hemoglobin E, abnormalities in ankaryin and spectrin (ovalocytosis and eliptocytosis), in glucose-6-phosphate dehydrogenase and pyruvate kinase, loss of the Gerbich antigen (glycophorin C) and the Duffy antigen on the erythrocytes, thalassemia and variations in the major histocompatibility antigen classes 1 and 2 and CD32 and CD36.

In 1995 a consortium - the malaria genome project (MGP) - was set up to sequence the genome of P. falciparum. The genome of the parasite mitochondrion was reported in 1995, that of the plastid (apicoplast) in 1996, and the sequence of the first nuclear chromosome (Chromosome 2) in 1998. The sequence of Chromosome 3 was reported in 1999 and the entire genome on 3rd October 2002. The ~24 megabase genome is extremely AT rich (~80%) and is organised into 14 chromosomes: just over 5300 genes were described.

Evolution and Plasmodium falciparum

Surprisingly, malaria parasites harbor a plastid similar to plant chloroplasts, which they acquired by engulfing (or being invaded by) a eukaryotic alga, and retaining the algal plastid as a distinctive organelle encased within four membranes. The apicomplexan plastid, or apicoplast, is an essential organelle, thought to be involved in the synthesis of lipids and several other compounds, and provides an attractive target for antimalarial drug development, particularly in light of the emergence of parasites resistant to chloroquine and other antimalarial agents.

Plasmodium falcipardum is often used an example for evolution. Since sickle-cell disease carriers are relatively resistant to malaria, and people from malaria-stricken countries are much more likely to have the sickle-cell trait, it is often given as an example to show how mutations are not inherently good or bad, but in different environments could have either negative or positive effects. Thus, if one lives in a malaria-striken part of the world, natural selection gives a net advantage to having the sickle-cell trait. Other hemoglobin polymorphisms, such as thalassemias and hemoglobin C are also suspected to have arisen as a genetic means to reduce the burden of malaria.

The protist, plasmodium falciparum, has evolved in more recent times. Most strains of malaria can be treated with chloroquine, however P. falciparum has developed resistance to this treatment. In addition the strain can be treated with a combination of quinine and tetracycline. There are strains of P. falciparum that have grown resistent to this treatment as well. Different strains of P. falciparum have grown resistant to different treatments. Often the resistance of the strain depends on where it was contracted. Many cases of malaria that come from parts of the Caribbean and west of the Panama Canal as well as the Middle East and Egypt can often be treated with chloroquin, since they have not yet developed resistance. Nearly all cases contracted in Africa, India, and southeast Asia have grown resistant to this medication and there have been cases in Thailand and Cambodia in which the strain has been resistant to nearly all treatments. Often the strain grows resistant to the treatment in areas where the use is not as tightly regulated.

External links

Overview

Blood slides

Case histories

Pathology due to Plasmodium falciparum

Brain

Spleen

Liver

Kidney