Malaria is caused by protozoan parasites called Plasmodia, belonging to the parasitic phylum Apicomplexa. More than 200 species of the genus Plasmodium (=plasma + eidos, form) have been identified that are parasitic to reptiles, birds, and mammals. Four Plasmodium species have been well known to cause human malaria, namely, P. falciparum, P. vivax, P. ovale, and P. malariae. A fifth one, P. knowlesi, has been recently documented to cause human infections in many countries of Southeast Asia. Very rare cases of malaria have been reported due to other species such as Plasmodium brasilianum, Plasmodium cynomolgi, Plasmodium cynomolgi bastianellii, Plasmodium inui, Plasmodium rhodiani, Plasmodium schwetzi, Plasmodium semiovale, Plasmodium simium and Plasmodium eylesi. All malaria parasites infecting humans probably jumped from the great apes (in case of P. knowlesi, macaques) to man.[See]
Phylum: Protozoa Subphylum: Apicomplexa
Class: Sporozoa Subclass: Coccidia
Order: Coccidiida Suborder: Haemosporina
Subgenera: Plasmodium, Laverania
Species: (affecting man)
Quartan group: P. (Plasmodium) malariae, P. (P.) brasilianum
Benign tertian group: P. (P.) vivax, P. (P.) cynomolgi, P. (P.) cynomolgi bastianellii
Malignant tertian group: P. (Laverania) falciparum
Ovale group: P. (P.) ovale, P. (P.) simium
Knowlesi group: P. (P.) knowlesi
Phylogenetic Trees of Plasmodia
Source: Krief S et al. On the Diversity of Malaria Parasites in African Apes and the Origin of P. falciparum from Bonobos. PLoS Pathog 2010;6(2): e1000765.[Full Text]
Subtypes of P. vivax: Plasmodium vivax is divided into two subtypes, a dominant form, VK210 and a variant form, VK247. This division is dependent on the amino acid composition of the circumsporozoite (CS) protein. A strain of P. vivax containing a variant repeat in its CS protein was first isolated in Thailand.[3,4]. The CS repeat of this variant strain (Thai VK247) differs at 6/9 amino acids within the repeat sequence found in all previously described P. vivax CS protein. Following this discovery, several studies have been conducted to evaluate the global distribution of variant VK247; it was detected in indigenous populations of China , Brazil , Mexico [7,8], Peru [8,9], and Papua New Guinea . It is known that the drug susceptibility of the VK247 subtype of P. vivax is slightly different than VK210 , as well as that Anopheles albimanus and Anopheles pseudopunctipennis differ in their susceptibilities to P. vivax circumsporozoite phenotypes. Anopheles albimanus is more susceptible to the VK210 subtype, whereas An. pseudopunctipennis is more susceptible to the VK247 subtype.
Two species of P. ovale: P. ovale has been found to exist in two forms, classic and variant, with the latter accounting for the higher parasite density among humans. A new study has now proposed that ovale malaria in humans is caused by two closely related but distinct species of malaria parasite, Plasmodium ovale curtisi (classic type) and Plasmodium ovale wallikeri (variant type), named so in honor of malaria researchers Christopher F. Curtis (1939-2008) and David Walliker (1940-2007). These two nonrecombining, genetically distinct species coexist, being sympatric in Africa and Asia. Splitting of the 2 lineages is estimated to have occurred between 1.0 and 3.5 million years ago in hominid hosts.[12-16] [More at The Lancet]
Molecular characteristics of malarial parasites have also been studied in India.
Distribution of Plasmodia: Nearly 85% of cases in Africa are caused by P. falciparum, the remaining cases being caused by the other three strains. P. vivax is now the most geographically widespread of the human malarias, occurring in much of Asia, Central and South America, the Middle East, where 70–90% of the malaria burden is of this species and the rest due to P. falciparum.[1,18] P. malariae causes sporadic infections in Africa, parts of India, western Pacific and South America, whereas P. ovale is restricted to tropical Africa, New Guinea, and the Philippines. P. knowlesi has been reported from South East Asian countries such as Malaysia, Thailand, Viet Nam, Myanmar and Phillippines.[19-23]
Analyses of the mtDNA data have revealed that P. knowlesi is derived from an ancestral parasite population that existed prior to human settlement in Southeast Asia, and underwent significant population expansion approximately 30,000–40,000 years ago. The results indicate that human infections with P. knowlesi are not newly emergent in Southeast Asia and that knowlesi malaria is primarily a zoonosis with wild macaques as the reservoir hosts. Ongoing ecological changes resulting from deforestation, with an associated increase in the human population, could enable this pathogenic species of Plasmodium to switch to humans as the preferred host.
|Comparison of Malaria Parasites [21,25-32]|
|P. falciparum||P. vivax||P. ovale||P. malariae||P. knowlesi|
|Global Distribution||80-90% of cases in Africa, 40-50% of cases in western pacific and SE Asia, 4-30% in S Asia, S America and rest of tropics||70-90% of cases in most of Asia and S America, 50-60% of cases in SE Asia and western pacific, 1-10% in Africa||8% of cases in parts of Africa, stray cases in Asia||2-3% in Africa, sporadic in Asia and S America||Reported from SE Asia; 70% of cases in some of those areas|
|Occurrence in India||30–90% of cases in Orissa, the NE states, Chattisgarh, Jharkhand, Madhya Pradesh, Bihar, and Andamans; <10% of cases in other areas||Nearly 50% of total malaria burden; predominant species in most parts other than P. falciparum dominant areas.||Stray cases reported from Delhi, Gujarat Kolkata, Orissa, and Assam||3-16% reported from some tribal areas, particularly Orissa; sporadic elsewhere; incidence may be higher||Not reported|
|Tissue schizogony||5-6 days||8 days||9 days||13 days||8-9 days|
|Erythrocytic phase||48 hours||48 hours||49-50 hours||72 hours||24 hours|
|Red cells affected||All||Reticulocytes||Reticulocytes||Mature RBC’s||?|
|Merozoites per tissue schizont||40000||Over 10000||15000||2000||?|
|Merozoites per red cell schizont||8 – 32||12 – 24||4 – 16||6 – 12||10-16|
|Relapse from persistent liver forms||No||Yes||Yes||No, but blood forms can persist up to 30 years||No|
|Fever pattern||Tertian, sub tertian||Tertian||Tertian||Quartan||Quotidian|
|Severe malaria||Up to 24%||Up to 22%||Very rare||Very rare||6-10%|
|See Comparison of Four Human Plasmodium species at CDC|
Ring Forms of Malaria Parasites on Thin Blood Smear (Courtesy: CDC DPDx Image Library)
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With the turn of the millennium, the genome of humans, the Anopheles mosquito and the P. falciparum parasite have been sequenced. Thus for the first time, a wealth of information is available for all the three species that comprise the life cycle of the malaria parasite and this would help in a better understanding of the interactions among the three species that have long been evolving together. The genome sequence of P. falciparum was published in Nature (Nature, Plasmodium genomics special issue, 3rd October 2002 See http://www.nature.com/nature/malaria/index.html) and of the mosquito Anopheles gambiae was published in the same week in Science (Science, The Mosquito Genome: Anopheles gambiae, 298:5591; 4th October, 2002 See http://nora.embl.de/ivica/publications/12364791.pdf). The human genome sequence was published simultaneously in Nature (Initial sequencing and analysis of the human genome. Nature 409, 860-921 (15 February 2001) Available at http://www.nature.com/nature/journal/v409/n6822/full/409860a0.html ) and Science (Science Special Issue, February 2001 Vol 291, Issue 5507, Pages 1145-1434. Available at http://www.sciencemag.org/content/vol291/issue5507/index.dtl16 ) in February 2001. The sequencing of the genes opens up new approaches to the development of drugs, vaccines, insecticides and insect repellents, as well as intervention into malarial transmission. Genetic tools will also enable sampling of parasite, mosquito, and human genomes in malaria affected areas to support the malaria control activities.
The Malaria genome:
The sequencing of P. falciparum resulted from an international collaboration established in 1996, comprising of NIAID (National Institute of Allergy and Infectious Diseases), the Wellcome Trust, the Burroughs Wellcome Fund and the U.S. Department of Defense. Sequencers worked at The Institute for Genomic Research (TIGR) in Rockville, MD, the Stanford Genome Center in Palo Alto, California, and the Wellcome Trust Sanger Institute in the United Kingdom. The lead investigator, Malcolm Gardner of TIGR, co-authored the Nature paper with 44 researchers working in sites in the United States, the United Kingdom and Australia.
The genome sequence of P. falciparum covers 22.8 million bases of DNA, split into 14 chromosomes. Within the genome, 5279 genes have been identified. Only 733 of the 5279 genes have been identified as enzymes.
Most of the biosynthetic pathways appear to be localized in the apicoplast, a structure within the cell that has its own genome and is similar to the chloroplasts of plants and algae. Although this genome encodes only 57 proteins, it is calculated that around 10 per cent of the proteins encoded by the nucleus may be destined for this structure. The genome sequence also identifies the molecules within the apicoplast that are the targets of several existing drugs, like antibiotics and may open many potential drug targets.
The parasite appears to lack some key biosynthetic pathways; for example, making or interconverting amino acids, making purines, two protein components of ATP synthase (a mitochondrial ATP-producing enzyme) and components of a conventional NADH dehydrogenase complex. It has also been proposed that the regulation of protein levels is controlled through mRNA processing and translation, rather than by gene transcription and this may be another potential drug target.
Regions near the ends of each chromosome of the P. falciparum genome are interesting. The genes residing here encode surface proteins or antigens that are sometimes recognized by the human immune system to stimulate immune response. But exchange of material between chromosome ends gives the parasite a great capacity for change and thereby immune evasion.
The Anopheles genome:
France was the first country to undertake a large-scale sequencing program for the Anopheles genome. As early as 1998, Genoscope and the Unit of Insect Biochemistry and Molecular Biology at the Institut Pasteur sequenced and analyzed the ends of 12,000 large genome fragments from a “bank” set up by Frank Collins at the University of Notre-Dame in the United States. Subsequent work of sequencing the 14,000 genes of the Anopheles was a collective effort of the Anopheles Gambiae Genome Consortium (AGGC) set up in March 2001 and was performed at Genoscope with funds from the French government and at the Celera Genomics Group in Rockville, MD. The strategy selected for the sequencing of the Anopheles’ 280 million bases (Megabases – Mb) was the “whole genome shotgun” method. The institutions contributing to the effort included NIAID, the Special Program of Research on Tropical Diseases of the World Health Organization; European Molecular Biology Laboratory of Germany; the Institute of Molecular Biology and Biotechnology in Crete; the Institut Pasteur in Paris; TIGR; and the universities of Iowa, Rome, Notre Dame, and Texas A&M. Celera’s Robert A. Holt heads a list of 123 authors on the Science paper, submitted on behalf of the AGGC.
Information from the Anopheles genome is giving researchers new insights into mosquito physiology and behavior. Identification of the mosquito genes involved in the parasite’s transmission, resistance to insecticides, the mosquito’s olfactory system, its immunity, its ability to digest blood, its choice of humans as a blood source etc should eventually lead to the development of ways to control the transmission of malaria by this vector.
Some fifty genes are known to be related to the mosquito’s resistance to insecticides and four of these have been identified.
Comparisons between the genome sequence of Drosophila fruit fly (obtained in year 2000) and that of the mosquito have helped in the discovery of the mosquito’s equivalent gene mechanism capable of blocking development of the parasite in the mosquito. This could be a potential target for preventing the development of the parasite.
The mosquito’s smell receptors, are probably implicated in the female Anopheles’ attraction to humans and a whole range of genes associated with smell has been discovered. This will considerably facilitate research on these receptors, and will probably result in the development of new repellents or new attractants. Furthermore, the possibility of a better understanding of the metabolism of the mosquito’s resistance to current insecticides could allow a more ecological use of these products.
- Gardner MJ et al. Genome sequence of the human malaria parasite Plasmodium falciparum Available at http://www.nature.com/nature/journal/v419/n6906/full/nature01097.html
- Holt RA et al. The Genome Sequence of the Malaria Mosquito Anopheles gambiae Science Vol 298; 4 October 2002 Available at http://nora.embl.de/ivica/publications/12364791.pdf
- The malaria genome unveiled
- Malaria genomes cracked
- Sequenced malaria genome exposes novel drug targets
- MALARIA GENOME DATABASES
- Plasmodium falciparum Genome Project
- The malaria genome — and beyond
- The Mosquito Genome: Anopheles gambiae
- Genome sequence of the mosquito Anopheles gambiae: the prospects
- Parasite, Mosquito Genomes Complete Malaria Picture
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