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Plasmodium (the genus of pathogens causing malaria)

Life > Eukaryotes > Chromalveolata > Alveolata > Apicomplexa > Haemosporida

Malaria infects 300-500 million and kills 1.5-2.7 million people each year, making it by far the most serious of the diseases spread by insects. The pathogens causing malaria are four species of Plasmodium and they are transmitted from person to person by mosquitoes of the genus Anopheles.

The Plasmodium species causing malaria

  • Plasmodium falciparum. Causes malignant tertian malaria, which kills through cerebral malaria or renal failure. Fever occurs about every 48 hours but this periodicity is often masked because the stages are not always synchronous. This periodicity is termed tertian because of fever on the first day, no fever on the second and then a return of fever on the third day. Plasmodium falciparum needs an average ambient temperature of at least 20ºC so is found mainly in warmer parts of the world.
  • Plasmodium vivax. Causes benign tertian malaria which rarely kills. This species is not found in tropical Africa mainly because black Africans lack the red cell surface Duffy antigen that P. vivax requires for cell invasion. It can exist in places with an average summer temperature of only 16ºC. Together with P. ovale is is considered a relapsing malaria, so named because it can remain in a dormant hypnozoite stage for very long periods (years) in the liver. The adaptive value of this ability is that the parasite can persist in areas that experience long winters with no opportunities for transmission.
  • Plasmodium ovale. Causes a rare tertian malaria with a long incubation period and relapses at three-month intervals. Found mainly in tropical Africa but with sporadic reports from elsewhere. Life P. vivax, it is a recurrent malaria with a dormant liver stage.
  • Plasmodium malariae. Causes quartan malaria with fever returning every 72 hours. It is remarkable in that it can persist in the blood of a host for decades at very low densities, but it does not have a dormant stage in the liver. Relapses can sometimes occur half a century after being infected.

All four species are found in regions all round the world but they are thought to have been introduced to the New World from Europe and Africa during the sixteenth century. The distributions of P. vivax and P. ovale rarely overlap.

The Anopheles vectors

There are about 422 species of Anopheles worldwide, many of them sibling species that can only be identified using genetic techniques. Of these, about 70 are malaria vectors but only about 40 are important. The ability to transmit Plasmodium parasites depends on

  1. the mosquito living long enough for the parasite to complete its development;
  2. the mosquito's propensity to feed on humans; and
  3. whether or not the mosquito is physiologically suitable for the parasite. However, most Anopheles are thought to be able to support normal development of at least one of the Plasmodium species.

Life cycle of Plasmodium in humans and mosquitoes

Host Place Stage Description
both skin of person biting The female mosquito punctures the persons skin and injects saliva containing Plasmodium sporozoites
person liver pre-erythrocytic schizogonous cycle (asexual) The sporozoites are carried in the blood to the person’s liver and enter liver parenchyma cells. The sporozoite grows through feeding on the cell contents and changes to a schizont which is the form that undergoes multiple division, termed schizogony. This process of schizogony in the liver cell produces 2000-40000 separate tiny individuals termed merozoites. A merozoite then either infects another liver cell and repeats the cycle or it passes out of the liver into the blood and enters the erythrocyte schizogonous cycle. The period in the liver lasts 6-16 days.
person blood stream erythrocyte schizogonous cycle (asexual) A merozoite enters an erythrocyte (red blood cell) and grows through feeding on the cell contents. The individual is transformed into a schizont that undergoes the process of schizogony to produce 6-24 merozoites (much less than the number produced in the liver). The cycle is usually repeated a number of times so that the number of infected erythrocytes in the blood stream increases enormously. The duration of the cycle is the duration between successive bouts of fever in the victim, each bout correlating with the simultaneous release of the merozoites from the cells. This is because the release stimulates the person’s immune system to produce cytokines which cause fever. Erythrocytes are killed by being infected and the remains are broken down in the spleen, a reason why the spleen is enlarged in people with malaria.
person blood stream gametocyte formation Merozoites eventually stop multiplying and transform into male and female individuals termed gametocytes.
both skin biting The mosquito bites the person, injecting saliva and sucking up blood containing the gametocytes. Any other Plasmodium stages such as merozoites are digested in the mosquito’s gut but the gametocytes survive.
mosquito gut gamete formation Female gametocytes transform into macrogametes, a process that includes the reduction of the chromosomes to the haploid number. The nucleus of the male gametocyte divides up into several elongate protoplasmic processes that radiate from the surface of the male gametocyte. Each of these processes becomes a male gamete termed a microgamete which is equivalent to a mammalian spermatozoon. The process by which the microgametes break away from the surface of the male gametocyte is termed exflagellation.
mosquito gut fertilisation A microgamete fertilizes a macrogamete to form a zygote.
mosquito gut ookinete formation The zygote transforms into a motile ookinete which penetrates the wall of the midgut and settles under the membrane separating the midgut from the haemocoel where it forms into a non-motile oocyst.
mosquito exterior of midgut Sporogony The oocyst grows and its contents divides into about 10000 elongate sporozoites. This process does not occur unless temperatures are from 16 to 33 ºC. The sporozoites burst out of the oocyst into the haemocoel and many of them find there way to the salivary glands.
both skin of person biting The cycle is repeated by the mosquito biting another person and injecting the infected saliva.

Prevention and control of malaria

The lesson from the now abandoned global malaria eradication campaign was that malaria cannot be dealt with as a single and uniform worldwide problem, susceptible to one global control strategy (Collins & Paskewitz 1995).

  • antiparasitic drugs.
  • Insecticides. Insecticidal control methods target a week link in the transmission cycle which is that the mosquito needs to stay alive for quite a long time for complete parasite development to take place. However, mosquitoes soon build up resistance to particular insecticides and so new, usually more expensive ones, constantly need to be formulated. Insecticides are used in three main ways for controlling mosquitoes:
    • Spraying of insecticide on larval habitats. When a large proportion of the larval habitat can be identified, larval control can be very effective.
    • Insecticide impregnated bed nets. Recent studies have shown that impregnation of bed nets with pyrethroid insecticides can be effective in controlling mosquitoes and preventing bites. However, in many cases this approach does not reduce the infection rate because the mosquitoes are feeding outdoors in the early evening before people have gone to bed.
    • Residual insecticides in home interiors. Formulations with long-term residual activity are sprayed on surfaces that the mosquito is likely to encounter such as walls in houses and huts. However, some species of Anopheles often rest outdoors after a blood meal.
  • Breeding habitat modification. Drainage, filling, levelling, intermittent flushing, and aquatic plant control are cost-effective options for removing larval aquatic breeding habitat. Economic development projects (e.g. building dams) need to ensure that they don't increase larval breeding habitat.
  • Biological control agents. There are a few successful cases of fish being introduced to water bodies to eat mosquito larvae. For instance, the North American fish Gambusia affinis reduced malaria incidence in Italy and Greece and its introduction into 3800 wells in India reduced the number of wells containing larvae by 75%.
  • Development of malaria vaccines. This has been complicated by both scientific and political difficulties and so far no effective vaccines are available.
  • Genetic modification. The idea here is to use DNA techniques to replace a highly competent vector population with one that is engineered to be an incompatible host for the malaria parasite. There has already been success in splicing into the genome of Anopheles stephensi a gene that provides resistance to Plasmodium. This gene encodes a peptide that seems to block receptors in the gut and salivary glands of the mosquito that are used by Plasmodium for replication . Experiments showed that mosquitoes with this gene were unable to infect mice with malaria. A similar exercise is now under way to splice this gene into the genome of Anopheles gambiae which is the main culprit for transmitting malaria in Africa (see news report in Science 293: 2370-2371, Sept. 2001). There is also a huge project underway to map the entire genome of A. gambiae. 

History of malaria

Links

References

  • Collins, F.H. & Paskewitz, S.M. 1995. Malaria: current and future prospects for control. Annual Review of Entomology 40: 195-219.

  • Gullan, P.J. & Cranston, P.S. 1994. The Insects: An Outline of Entomology. Chapman & Hall, London.

  • Service, M.W. 1993. Mosquitoes (Culicidae). In: Medical Insects and Arachnids (eds R.P. Lane and R.W. Crosskey). Chapman and Hall, London, pp. 120-240.

Text by Hamish Robertson