Malaria


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life-cycle-of-Plasmodium-FalciparumThis series of graphics have been designed to explain how malaria causes pathology, the immune responses which the host produces and the unique strategies which the malaria parasite has developed to evade the host immune system allowing it to cause repeated infection.

Lifecycle of Plasmodium falciparum
This graphic illustrates the full malaria lifecycle from time of inoculation of sporozoites from the anopheles mosquito into the human host, the series of events that follow, ending with the sexual reproduction which occurs once again in the mosquito following a subsequent blood meal.

Adaptive-immune-response-to-plasmodium-falciparumAdaptive immune response to Plasmodium falciparum
Specific immune responses are required to control the infection at multiple points in the parasite life cycle. Both humoral and cell-mediated responses are invoked. Antibodies to sporozoites are the first immune response designed to prevent the parasite from reaching the liver. If they get to the liver then within the liver CD8+ cytotoxic T lymphocytes destroy infected hepatocytes via HLA class I antigen recognition. Thereafter, antibodies to free merozoites work to block infection of new erythrocytes. If the parasite has succeeded in infecting more erythrocytes antibodies to parasite proteins on the surface of infected erythrocytes bring about removal by phagocytosis, especially in the spleen. The final response is the formation of antibodies to gametocytes which hinders the development of parasites in the mosquito vector.

Adhesion-of-infected-erythrocytes-to-vascular-endothelial-cellsAdhesion of infected erythrocytes to vascular endothelial cell
Infected erythrocytes express parasite derived PfEMP-1 proteins on the cell surface. These proteins have a high affinity for membrane receptors such as CD36 and ICAM-1 expressed on vascular endothelial cells. This binding of infected erythrocytes, known as sequestration, allows escape from circulation to the spleen where they would be destroyed and removed. The resulting occlusion of capillaries has been partially implicated  in severe complications such as cerebral malaria, kidney disease and respiratory distress.

innate-immune-response-to-plasmodium-falciparumInnate immune response to Plasmodium falciparum
Control of the malaria parasite growth is dependent on a strong cell-mediated immune response mainly due to the pro-inflammatory cytokines IL-12 and INF-g. Furthermore, the innate immune responses to merozoites occurs by stimulation of toll like receptors, namely TLR2, which binds GPI and TLR9 that binds parasite dsDNA. Once these receptors are stimulated they cause secretion of the pro-inflammatory cytokines IL-1, IL-6 and TNF-a that cause fever, the hallmark of malaria infections.

Malaria suppression of immune responses
The blood stage of malaria leads to suppression of cell-mediated immune responses by the reduction of IL-12 and the increase of TGF-b and IL-10. These further result in suppression of Th1 cell activation and INF-g secretion.

Antigenic variation of merozoite surface proteins and erythrocyte surface proteins
One of the immune evasion strategies that malaria has developed involves antigenic polymorphisms and clonal antigenic variation. Antibodies and T cell receptors recognise specific pathogen derived epitopes. Resultantly, by parasites varying their allelic expression they are able to dodge host immune recognition. Parasite antigenic diversity involves the expression of numerous antigenically distinct alleles of a particular gene in different parasite populations, due to selection by immune pressure. Parasites expressing mutant alleles which create antigens not recognised by host antibodies and T cell receptors are free to selectively multiply.

 

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International Union of Immunological SocietiesUniversity of South AfricaInstitute of Infectious Disease and Molecular MedicineScience Education PrizesElizabeth Glazer Pediatric Aids FoundationAlere