Evolution of Genetic Resistance/Susceptibility to Malaria Infection

Kanjaksha Ghosh, Indian Council of Medical Research, Mumbai, India
Kinjalka Ghosh, Indira Gandhi Government Medical College, Nagpur, India

Published online: August 2012

DOI: 10.1002/9780470015902.a0022492

Severe malaria infection still kills more than 2.7 million people across the globe every year. Of the few infections which has shaped human genome over the millennia through the process of natural selection, malaria infection has left its imprints on human genome. Genetic studies on malarial resistance started in the late 1940s with demonstration of protection against malaria in carriers of several haemoglobinopathy genes and further demonstration of increasing prevalence of such genes across the malarious areas of the world. As malaria parasites pass a significant period of its life inside the red cell, many red cell proteins and their genes were studied for polymorphic variants which offers protection against such infection. Total absence of Plasmodium vivax malaria in Western Africa and its linkage with total absence of red cell Duffy antigen is a case in point. Subsequently as a rational extension of the above idea, association of resistance or susceptibility to severe malarial infection were studied with relation to genes of innate immunity, adoptive immunity, cytokine genes, adhesion molecules, coagulation proteins, proteins involved in systemic inflammatory reactions etc. Innumerable studies have shown various kinds of association. However, at present the interest has shifted towards genome wide association studies with malarial infection. Present review stops short of genome wide association and presents a snapshot view of genome association with malaria infection.

Key Concepts:

  • The immune system of man has evolved to fight pathogens like malaria parasite.
  • Pathogens have exerted intense selective pressures on the evolution of the immune system of man.
  • Key elements of the adaptive immune system, such as antigen receptors and major histocompatibility complex molecules, show evidence of such selective pressures.
  • Mutation is the key genetic mechanism underlying the co-evolution of the immune system and pathogens.
  • Evolutionary adaptation to malaria involves many more aspects than modification of adoptive and Innate Immune system.
  • Owing to complex life cycle of the parasite and its specific requirements of nutrition and need for protection during its growth, the parasite vulnerability increases due to changes in Nutrient (haemoglobin), Host Enzyme system (Oxidant damage), changes in specialised receptors for entry into cells (Red cells, Hepatocytes) and its ability to adhere to Key cells (Endothelium).
  • Product of metabolism of malaria parasite (Hemozoin) exerts strong immunomodulatory effect.
  • As malaria parasite from different regions of the world exerted selection pressure on different population groups with different genetic endowment (polymorphisms), this resulted in evolution of different key resistant molecules against malaria in different parts of the world.

Keywords: falciparum malaria; vivax malaria; red cell; haemoglobin; polymorphisms; HLA antigens; cytokine genes; adhesion molecules; endothelial cells; toll like receptors; haemozoin; immunomodulation

Figure 1. Life cycle of malaria parasite and polymorphisms of host/parasite genes conferring resistance susceptibility to infection. (1) Spread of malaria infection from vector (Anopheline mosquito) depends on (i) Population bottleneck, that is, a minimum number of mosquitoes are needed in a given area for transmission; (ii) efficiency of the particular species for transmission of malaria; (iii) resistance of the vector to insecticides. Vector inject sporozoites in the host (man) by biting them. Sporozoites can be neutralised by IgG1 and IgG3 antibodies against PfLSA-1, PfLSA-2 antigens which are dependent on host HLA. Sporozoites finally attach itself to LRP receptor and heparan sulphate associated receptor on liver cells and enter the liver cells. (2) In the hepatic cytoplasm the parasite undergoes pre- and exoerythrocytic schizogony. Efficiency of this process depends on many hitherto unknown factors in liver cells which needs to be worked out. Merozoites coming out of liver cells and red cells infect fresh batch of red cells but they can be dealt with HLA-B53 restricted cytotoxic T cells, Toll-like receptors, cytokine S and other HLA antigens. (3) Entry of merozoites in the red cell is controlled by various receptors. (4) Some of them are blood group antigens. Once merozoites enter red cells, the erythrocytic schizogony is restricted or the infected erythrocytes become more vulnerable to phagocytes due to various haemoglobinopathies, red cell enzyme defects or red cell membrane defects as well as iron transporters. Infected red cells interact with endothelial cells through various receptors. This interaction modulates endothelial function, alters blood coagulation and also activates enos. Hemzoin pigment released from infected red cells cause strong immune suppression. Haemoglobin–Haptoglobin complex engage monocytes through specific receptors. Various Fc and complement receptors also engage monocyte. Haem-oxygenase in monocytes produce cytotoxic bilirubin and carbon monoxide from haemoglobin.
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Related Sub-Topics:

Infection | Cytokines | Acquired (Adaptive) Immunity | Innate Immunity | Adaptive Evolution | Protein Evolution | Selection and Variation | Human Evolution | Inter-Individual Variation and Polymorphism
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Article Title: Evolution of Genetic Resistance/Susceptibility to Malaria Infection
 
How to Cite close
Ghosh, Kanjaksha, and Ghosh, Kinjalka(Aug 2012) Evolution of Genetic Resistance/Susceptibility to Malaria Infection. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022492]