Plasmodium falciparum
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| Plasmodium falciparum | ||||||||||||
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| Plasmodium falciparum Welch, 1897 |
Plasmodium falciparum<i> 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.
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Background
Malaria is caused by infection with protozoa of the genus <i>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 exflagelating. 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 Northhampton 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 2 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's encouraged his 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.
Vaccine prospects presently (2004) appear slim. The parasites have a profound effect on the immune system frequently inducing total 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.
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.
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 anaemia could offer some protection to malaria. This hypothesis has since been confirmed and has been extended to haemoglobin C and haemoglobin E, abnormalities in ankaryin and spectrin (ovalocytosis and eliptocytosis), in glucose-6-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.
Plasmodium falciparum genome project
In 1995 a consortium - the malaria genome project (MGP) - was set up to sequence the genome of P falciparum. The genome of the mitochondrion was reported in 1995, that of the plastid 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.
Within a year of the publication of Chromosome 2, the accuracy of its annotation was being questioned. Errors, including in frame stop codons, were also found in Chromosome 3. In 2001 a revision of Chromosome 2, with experimental confirmation, was published by Huestis and Fisher using a new method of largely manual annotation. Given the success of the results of Chromosome 2, Huestis and Coppel decided to independently annotate the entire genome and considerable progress to this goal had been made by the time the MGP published. When the MGP reported, it was immediately clear that the error rate was again significant – of the order of 30%. There were initially some difficulties with the independent annotation but this was completed in 2004.
External links
Overview
- Introductory (http://www.tulane.edu/~wiser/protozoology/notes/malaria.html)
- Oveview (http://www.ratsteachmicro.com/Malaria_notes/HCOE_CAI_Review_Notes_Malaria.htm)
- Malaria biology (http://www.tulane.edu/~wiser/malaria/cmb.html)
- Life cycle cartoon (http://www.roche.nl/ziektebeeld/malaria/malaria2.gif)
Blood slides
- Blood forms (http://home.austarnet.com.au/wormman/paraimg/pfalcipt.jpg)
- Blood forms (http://home.austarnet.com.au/wormman/paraimg/pfalcipm.jpg)
- Blood forms (http://www.yamagiku.co.jp/pathology/photo/photo206-7.htm)
- Blood forms (http://www.yamagiku.co.jp/pathology/photo/photo206-8.htm)
- Multiple blood forms (http://www.yamagiku.co.jp/pathology/photo/photo206-1.htm)
- Female gametocyte (http://home.austarnet.com.au/wormman/paraimg/pfalcipg.jpg)
- Female gametocyte (http://medschool.sums.ac.ir/users/parasito/Blood%20and%20tissue%20protozoa/Plasmodium%20%20falciparum%20gametocyte2.JPG)
- Male gameocyte exflagelating (http://www.hh.schule.de/ghb/new_page/projekte/infektionskrankheiten/group5/malariapic.jpg)
Case histories
- Case 1 (http://www.med-chem.com/Para/Prob%20of%20Month/Prob%20of%20Month%2038%20February%2004.htm)
- Case 2 (http://www.med-chem.com/Para/Prob%20of%20Month/Prob%20of%20Month%2031%20July%2003.htm)
- Case 3 (http://www.yamagiku.co.jp/pathology/case/case206.htm)
- Case 4 (http://www.yamagiku.co.jp/pathology/case/case129.htm)
Pathology due to Plasmodium falciparum
Brain
- Gross pathology (http://www.vh.org/adult/provider/pathology/CNSInfDisR2/Text/165.html)
- Low power H & E stain (http://www.neuroanatomy.hpg.ig.com.br/Histopathology%20of%20malaria%20of%20brain.%20Mature%20schizontsss_2.jpg)
- High power H & E stain showing parasite adherence to the vessel walls (http://www.neuroanatomy.hpg.ig.com.br/Histopathology%20of%20malaria%20of%20brain.%20Mature%20schizonts._2.jpg)
Spleen
- Gross pathology (http://www.yamagiku.co.jp/pathology/photo/photo206-2.htm)
- Low power H & E (http://oac.med.jhmi.edu/Pathology/Idmicro/Parasite/037A_Full.html)
- Smear preparation (http://www.yamagiku.co.jp/pathology/photo/photo206-3.htm)
- Smear preparation (http://www.yamagiku.co.jp/pathology/photo/photo206-4.htm)
Liver
- Low power H & E (http://www.yamagiku.co.jp/pathology/photo/photo206-5.htm)
- High power H & E (http://medschool.sums.ac.ir/users/parasito/Blood%20and%20tissue%20protozoa/Malaria-schizont%20in%20liver500X.JPG)
Kidney
- Low power H & E (http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/07MN_medulla_L.gif)
- High power H & E (http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/01MN_Ex_L.gif)
- High power H & E (http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/05MN_Ex_HE3_L.gif)
- Membrane stain (http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/02MN_Ex_PAM1_L.gif)
- Membrane stain (http://www.med.niigata-u.ac.jp/npa/Lectures/Images/Slides/MN/06MN_Ex_PAM3_L.gif)
Plasmodium falciparum genome data
- Genome (http://www.wehi.edu.au/MalDB-www/who.html)
- Other genome projects and additional information (http://plasmodb.org/links.shtml)