Plasmodium falciparum

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 an infection with protozoa of the genus Plasmodium. The name malaria comes from the Italian male aria, 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.

Plasmodium Life Cycle
When an infected mosquito bites a human, sporozoites enter the human circulation. These go to and penetrate the liver cells, where they asexually reproduce, via the process of schizogony. This intracellular, asexually dividing form of the parasite is known as a schizont, and because this schizont is in liver cells and not RBCs, it is known as the exoerythrocytic schizont stage.

''Aside: In Plasmodium vivax and Plasmodium ovale species, the development of the schizont is retarded, and a "resting" stage of the parasite, called the Hypnozoite, is formed. This is NOT the case in Plasmodium falciparum.''

When the hepatocytes burst, exoerythrocytic schizonts release merozoites into the blood, which are capable of infecting erythrocytes. Inside the erythrocytes, the merozoites develop into ring-like trophozoites, which then form the erythrocytic schizonts.

Mature erythrocytic schizonts form merozoites again by breaking apart inside the erythrocytes. These merozoites are a transient intracellular form, either rapidly infecting new red blood cells to complete the erythrocytic cycle, or dying. In addition, when infection of new blood cells occurs, instead of forming trophozoites the parasites may grow into the immature gametocytes. These can be taken up in the bloodmeal of a mosquito, causing the parasite to go back to the intermediate host and completing the life cycle.

Treatment and drug resistance
Attempts to make synthetic antimalarials began in 1891. Atabrine 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. In the late 1930s, the Germans developed chloroquine, which went into use in the North African campaigns. Mao Zedong 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. In 1976 P. falciparum was successfully cultured in vitro for the first time which facilitated the development of new drugs substantially.

Vaccination
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 Staphylococcus 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". The comma shaped dots can also appear as pear shaped blotches.

Plasmodium and the human genome
In the 50,000 years since Plasmodium first infected humans, the presence of the parasite in human populations has altered the human genome in a multitude of ways, as humans have been forced to develop resistance to the disease. Beet, a doctor working in Southern Rhodesia (now Zimbabwe) in 1948, first suggested that sickle-cell disease could offer some protection to malaria. This suggestion was reiterated by J. B. S. Haldane in 1949 who suggested that thalassaemia could provide similar protection. This hypothesis has since been confirmed and has been extended to hemoglobin C and hemoglobin E, abnormalities in ankyrin and spectrin (ovalocytosis, elliptocytosis), in glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency, loss of the Gerbich antigen (glycophorin C) and the Duffy antigen on the erythrocytes, thalassemias and variations in the major histocompatibility complex 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 (see endosymbiotic theory). 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 existing antimalarial agents.

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 resistant 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.

Plasmodium falciparum is often used as 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-stricken 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.

Overview

 * Introductory
 * Overview
 * Malaria biology
 * Life cycle cartoon

Spatial distribution

 * Malaria Atlas Project

Blood slides

 * Blood forms
 * Blood forms
 * Blood forms
 * Blood forms
 * Multiple blood forms
 * Female gametocyte
 * Female gametocyte
 * ncbi.nlm.nih.gov

Case histories

 * Case 1
 * Case 2
 * Case 3
 * Case 4

Pathology due to Plasmodium falciparum

 * Brain
 * Gross pathology
 * Low power H & E stain
 * High power H & E stain showing parasite adherence to the vessel walls


 * Spleen
 * Gross pathology
 * Low power H & E
 * Smear preparation
 * Smear preparation


 * Liver
 * Low power H & E
 * High power H & E


 * Kidney
 * Low power H & E
 * High power H & E
 * High power H & E
 * Membrane stain
 * Membrane stain

Plasmodium falciparum genome data



 * PlasmoDB: The Plasmodium Genome Resource
 * GeneDB Plasmodium falciparum
 * Genome

Other

 * Colombian scientists develop computacional tool to detect the plasmodium falciparum (in spanish)

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