Evolution of Genetic Resistance/Susceptibility to Malaria Infection


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‚Äźevolution 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.



Allen SJ, O'Donnell A, Alexander ND et al. (1999) Prevention of cerebral malaria in children in papua New Guinea by South East Asian Ovalocytosis band 3. American Journal of Tropical Medicine and Hygiene 60: 1056–1060.

Allison AC (1954) Protection afforded by sickle cell trait against subtertian malarial infection. British Medical Journal 1: 290–294.

Awandare GA, Martinson JJ, Were T et al. (2009) MIF (Macrophage migration Inhibitory Factory). Promoter polymorphisms and susceptibility to severe malarial anaemia. Journal of Infectious Diseases 200: 629–637.

Ayi K, Min‐Oo G, Serghides L et al. (2008) Pyruvate kinase deficiency and malaria. New England Journal of Medicine 358: 1805–1810.

Casal Pascal C, Allen S, Allen A et al. (2001) Codon 125 polymorphism of CD 31 and susceptibility to malaria. American Journal of Tropical Medicine and Hygiene 65: 736–737.

Chakraworthy MR, Wilcocks L, Urban B et al. (2007) Systemic lupus erythematosus associated defects in the inhibitory receptor FcrIIb reduces susceptibility to malaria. Proceedings of the National Academy of Sciences of the USA 104: 7169–7174.

Clark P and Wu O (2011) ABO blood groups and thrombosis a causal association but is there value in screening? Future Cardiology 7: 191–201.

Cooke GS, Ancan C, Walley AJ et al. (2003) Association of Fe gamma receptor IIa (CD‐32) polymorphism with severe malaria in West Africa. American Journal of Tropical Medicine and Hygiene 69: 565–568.

Cramer JP, Mockenhanbt FP, Ehrhardts et al. (2004) Inos promoter variants and severe malaria in Ghanaian children. Tropical Medicine & International Health 9: 1074–1080.

Cserti CM and Dzik WH (2007) The ABO blood group system and Plasmodium falciparum malaria. Blood 110: 2250–2258.

Diakite M, Clark TG, Auburn S et al. (2009) A genetic association study in The Gambia using tagging polymorphisms in the major histocompatibility complex (MHC) class III region implicates a HLA‐B associated transcript 2 (BAT2) polymorphism in severe malaria susceptibility. Human Genetics 125: 105–109.

Elagib AA, Kider AO, AKerstrom B and Elbashir M (1998) Association of the haptoglobin phenotype (1‐1) with falciparum malaria in Sudan. Transactions of the Royal Society of Tropical Medicine and Hygiene 92: 309–311.

Fernandez‐Reyes D, Craig AG, Kyes SA et al. (1997) A high frequency of African coding polymorphism in the N terminal domain of ICAM 1 predisposing to cerebral malaria in Kenya. Human Molecular Genetics 6: 1357–1360.

Ferwerda B, McCall MBB, Alonso S et al. (2007) TLR4 polymorphism, infectious disease and evolutionary pressure during migration of modern humans. Proceedings of the National Academy of Sciences of the USA 104: 16645–16650.

Fortin A, Stevenson MM and Gros P (2002) Susceptibility to malaria as complex trait: big pressure from a tiny creature. Human Molecular Genetics 11: 2469–2478.

Gandhi M (2007) Complement receptor 1 and molecular pathogenesis of malaria. Indian Journal of Human Genetics 13: 39–47.

Genton B, al‐Yaman F, Mgone CS et al. (1995) Ovalocytosis and cerebral malaria. Nature 378: 564–565.

Ghosh K (2008) Evolution and selection of human leucocyte antigen alleles by Plasmodium falciparum infection. Human Immunology 68: 855–860.

Ghosh K and Shetty S (2008) Blood coagulation in falciparum malaria – a review. Parasitology Research 102: 571–576.

Ghosh K, Shetty S and Mota L (2008) Falciparum malaria selected while HIV1 slaughtered. Indian Journal of Human Genetics 14: 70.

Giha AH, Nasr A, Ekstrom M et al. (2010) Association of a single nucleotide polymorphism in the C‐reactive protein gene (‐286) with susceptibility to Plasmodium flaciparum malaria. Molecular Medicine 16: 27–33.

Hill AV (1998) The immunogenetics of human infectious diseases. Annual Review of Immunology 16: 593–617.

Hill AVS, Allsopp CEM, Kwiat Kowski DP et al. (1991) Common West African HLA antigens are associated with protection against severe malaria. Nature 352: 595–600.

Khor CC, Vannberg FO, Chapman SJ et al. (2010) CISH and susceptibility to infectious disease. New England Journal of Medicine 362: 2092–2101.

Kuesap J, Hirayama K, Kikuchi M, Ruangweera yut R and Na‐Bangchang K (2010) Study on association between genetic polymorphism of haem oxygenase‐7 tumour necrosis factor, cadmium exposure and malaria pathogeneity and severity. Malaria Journal 9: 260–265.

Kun JF, Mord muller B, Perkins DJ et al. (2001) Nitric oxide synthase 2 (Lambarene) (G‐954C) increased nitric oxide production and protection against malaria. Journal of Infectious Diseases 184: 330–336.

Kwiatkowski DP (2005) How malaria has affected the human genome and what human genetics can teaches about malaria. American Journal of Human Genetics 77: 171–190.

Langlois MR and Delanghe JR (1996) Biological and clinical significance of haptoglobin polymorphism in humans. Clinical Chemistry 42: 1589–1600.

Luty AJ, Kun JF and Kremsner PG (1998) Mannose binding lectin plasma levels and gene polymorphisms in Plasmodium falciparum malaria. Journal of Infectious Diseases 178: 1221–1224.

Madan N, Sharma S, Sood SK, Colah R and Bhatia LH (2010) Frequencing of β thalassaemia trait and other haemoglobinopathies in Northern and Western India. Indian Journal of Human Genetics 16: 16–25.

Maier AG, Duraisingh MT, Reeder JC et al. (2003) Plasmodium falciparum erythrocyte in various through glycophorin C and selection for Gerbich negativity in human populations. Nature Medicine 9: 87–92.

Minanag JT, Gyan BA, Anchang JK et al. (2004) Haptoglobin phenotypes and malaria infection in pregnant women at deliver in Western Cameroon. Acta Tropica 90: 107–114.

Mockenhampt FP, Cramer JP, Hamann L et al. (2006) Toll like receiptor (TLR) polymorphisms in African children : Common TLR variants predispose to severe malaria. Proceedings of the National Academy of Sciences of the USA 103: 177–182.

Modiano D, Lunomi G, Sririma BS et al. (2001) Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414: 305–308.

Moestrup SK and Moller HJ (2004) CD163: a regulated hemoglobin scavenger receptor with role in anti inflammatory response. Annals of Medicine 36: 347–354.

Naka I, Nishida N, Patrapotikul J et al. (2009) Identification of a haplotype block in the 5q31 cytokine gene cluster associated with the susceptibility to severe malaria. Malaria Journal 232. doi: 10.1186/1475‐2875‐8‐232.

O'Donnell A, Prem Wardhena A, Arambepola M et al. (2009) Interaction of malaria with a common form of severe thalassaemia in an Asian population. Proceedings of the National Academy of Sciences of the USA 106: 18716–18721.

Pauri A, Urban BC, Kai O et al. (2001) A nonsevere mutation in CD36 gene is associated with protection against severe malaria. Lancet 357: 1502–1503.

Pichyankul S, Yongvantichit K, Kum‐arb U et al. (2004) Malaria blood stage parasites activate human plasmacytic dendritic and murine dendritic cells through a Toll like receptor 9 depcelet pathway. Journal of Immunology 172: 4926–4933.

Qyaye IK, Ekuban FA, Goke BQ et al. (2000) Haptoglobin 1‐1 is associated with susceptibility to severe Plasmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 94: 216–219.

Randall LM, Kenangalem E, Lampah DA et al. (2010) A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland Papuan children and adults. Malaria Journal 9: 302.

Ruwende C, Khoo SC, Snow RW et al. (1995) Natural selection of hemi and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 376: 246–249.

Shi YP, Nahlan BL, Kariuki S et al. (2005) Fcr receptor II a (CD32) polymorphism is associated with protection of infants against high density Plasmodium falciparum infection VII Asmebo bay Cohert project. Journal of Infectious Diseases 184: 107–111.

Singh B, Sung KL, Matusop A et al. (2004) A large focus of naturally acquired P. knowlesi infection in human beings. Lancet 363: 1017–1023.

Teye K, Quaye IK, Khoda Y et al. (2003) A‐61C and C‐101 G, Hp gene promoter polymorphisms are respectively, associated with a haptogloblinaemia and hypohaptoglobinaemia in Ghana. Clinical Genetics 64: 439–443.

Timman C, Evans JA, Konig IR et al. (2007) Genome wide linkage analysis of malaria infection intensity and mild disease. PLoS Genetics 3: e48.

Tournamille C, Colin Y, Cartron JP and Le Van Kim C (1995) Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy negative individuals. Nature Genetics 10: 224–228.

Urban BC and Todryk S (2006) Malaria pigment paralysis dendritic cells. Journal of Biology 5: 4.

Verra F, Mangano VD and Modiano D (2009) Genetic S of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome wide association studies. Parasite Immunology 31: 234–253.

Weatherall DJ (2008) Genetic variation and susceptibility to infection: the red cell and malaria. British Journal of Haematology. 141: 276–286.

Further Reading

Bellamy R, KwiatKowski D and Hill AV (1998) Absence of an association between intra cellular adhesion molecule 1, complement receptor 1, and interleukin1 receptor antagonist gene polymorphism and severe malaria in Western African population. Transactions of the Royal Society of Tropical Medicine and Hygiene 92: 312–316.

Greenwood B (2002) The molecular epidemiology of malaria. Tropical Medicine & International Health 7: 1012–1021.

Gupta S and Hill AVS (1995) Dynamic interaction in malaria: host hetero geneity meets parasite polymorphism. Proceedings of the Royal Society of London B Biological Sciences 261: 271–277.

Jenkins PV and O'Donnell JS (2006) ABO blood group determine plasma von Willebrand factor levels a biologic function after all? Transfusion 46: 1836–1844.

Luzzato l, Mehta A and Vulliamy T (2012) Glucose 6‐phosphate dehydrogenase. In: Scriver CR, Beandet AL, Sly WS et al. (eds) The Metabolic and Molecular Basis of Inherited Disease, pp. 4517–4554. New York: McGraw Hill.

Miller LH, Mason SJ, Clyde DF and Mc Ginniss MH (1976) The resistance factor to Plasmodium vivax in Blacks. New England Journal of Medicine 295: 302–304.

Min OoG, Fortin A, Tam MF et al. (2003) Pyruvate kinase deficiency in mice protects against malaria. Nature Genetics 35: 357–362.

Osafo‐Addo AD, Koram KA, Oduro AR et al. (2008) HLA‐DRB1*04 Allele is associated with severe malaria in northern Ghana. American Journal of Tropical Medicine and Hygiene 78: 251–255.

Yamazaki A, Yasunami M, Ofori M et al. (2011) Human leukocyte antigen class I polymorphisms influence the mild clinical manifestation of Plasmodium falciparum infection in Ghanaian children. Human Immunology 72: 881–888.

Web Links

URL. Mlaria GEN., http://www.malariagen.net/

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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]