Researchers characterize potential protein targets for malaria vaccine
Every day 2000 children die from malaria in Africa alone. The infection is transmitted from human to human by biting mosquitoes. Despite many years of effort, a vaccine is still not available to fight the deadly disease. Once injected by a mosquito, parasites migrate to the liver where they mature and then their sporozoites (infective cells) are released into the blood, causing disease and fatal complications. Human malaria is caused by Plasmodium falciparum, a unicellular protozoan parasite that is transmitted by Anopheles mosquitoes. An infectious mosquito injects saliva containing sporozoite forms of the parasite and these then migrate from the skin to the liver, where they establish an infection. Many intervention strategies are currently focused on preventing the establishment of infection by sporozoites. Clearly, an understanding of the biology of the sporozoite is essential for developing new intervention strategies. Sporozoites are produced within the oocyst, located on the outside wall of the mosquito midgut, and migrate after release from the oocysts to the salivary glands where they are stored as mature infectious forms. Comparison of the proteomes of sporozoites derived from either the oocyst or from the salivary gland reveals remarkable differences in the protein content of these stages despite their similar morphology. The changes in protein content reflect the very specific preparations the sporozoites make in order to establish an infection of the liver. Analysis of the function of several previously uncharacterized, conserved proteins revealed proteins essential for sporozoite development at distinct points of their maturation.
Researchers characterized a large number of parasite proteins that may prove useful in the development of a human malaria vaccine. A promising method for vaccination is to sufficiently weaken these parasites such that they invade liver cells and stimulate an immune response, but don’t develop further. This can be achieved by genetically inactivating individual parasite genes that are active during the parasite’s growth in the liver. The researchers achieved this by modifying the proteins essential for sporozoite development, which their study identified. Collaborators had previously shown how to successfully vaccinate mice using a rodent malaria which had one of these liver stage genes removed, specifically p36p.
A related article shows the first transition of such a vaccination from the rodent system to humans, by inactivating the equivalent gene (p52) in the major human malaria parasite, P. falciparum. Similar to the results with the rodent parasite, these human parasites are unable to develop in liver cells. This is the first time that genetic modification of a human parasite results in its growth arrest in a liver cell, opening up promising possibilities for its use as a human vaccine. These studies show how results obtained in rodent models of malaria can be pipelined to form the basis for clinical development of anti-malaria vaccines in humans.
Proteomic Profiling of Plasmodium Sporozoite Maturation Identifies New Proteins Essential for Parasite Development and Infectivity. PLoS Pathog 4(10): e1000195
Plasmodium falciparum sporozoites that develop and mature inside an Anopheles mosquito initiate a malaria infection in humans. Here we report the first proteomic comparison of different parasite stages from the mosquito – early and late oocysts containing midgut sporozoites, and the mature, infectious salivary gland sporozoites. Despite the morphological similarity between midgut and salivary gland sporozoites, their proteomes are markedly different, in agreement with their increase in hepatocyte infectivity. The different sporozoite proteomes contain a large number of stage specific proteins whose annotation suggest an involvement in sporozoite maturation, motility, infection of the human host and associated metabolic adjustments. Analyses of proteins identified in the P. falciparum sporozoite proteomes by orthologous gene disruption in the rodent malaria parasite, P. berghei, revealed three previously uncharacterized Plasmodium proteins that appear to be essential for sporozoite development at distinct points of maturation in the mosquito. This study sheds light on the development and maturation of the malaria parasite in an Anopheles mosquito and also identifies proteins that may be essential for sporozoite infectivity to humans.
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Tags: Biology, Health, Malaria, Medicine, Microbiology, Parasitology, Science, Vaccines
