Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pathogenesis of malaria

Danny A Milner, Jr, MD
Section Editor
Johanna Daily, MD, MSc
Deputy Editor
Elinor L Baron, MD, DTMH


Understanding the pathogenesis of malaria requires investigation of mechanisms including parasite invasion, parasite biology, and host defense. The parasite life cycle illustrates the interplay of parasite and host interactions (figure 1). Pathogenesis of Plasmodium falciparum is the area of greatest study, since this species causes the most severe clinical disease (other species include P. ovale, P. vivax, P. malariae, and P. knowlesi). P. knowlesi malaria can also cause life-threatening illness [1], and, although rare, severe illness (including severe respiratory disease and anemia) and death due to P. vivax have been reported.

Issues related to the pathogenesis of malaria will be reviewed here. Issues related to epidemiology, clinical manifestations, diagnosis, and treatment are discussed in detail separately. (See related topics.)


Life cycle — Human malaria occurs by transmission of Plasmodium sporozoites via a bite from an infected anopheline mosquito (figure 1). The sporozoites travel from the salivary glands of the mosquito through the bloodstream of the host to the liver, where they invade hepatocytes. These cells divide many 1000-fold until mature tissue schizonts are formed, each containing thousands of daughter merozoites. This exoerythrocytic stage is asymptomatic.

The liver schizonts rupture after 6 to 30 days; 98 percent of patients experience liver schizogony by 90 days (there is typically a longer liver phase in species other than P. falciparum). This event releases thousands of merozoites into the bloodstream, where they invade red blood cells (the erythrocytic or asexual stage). P. falciparum may invade any red cell, while P. vivax and P. ovale prefer the younger, slightly larger reticulocytes. The merozoites mature successively from ring forms to trophozoites to mature schizonts (asexual forms) over 24 hours (P. knowlesi), 48 hours (P. vivax, P. ovale, P. falciparum), or 72 hours (P. malariae). Within red blood cells, the parasites digest hemoglobin. As hemoglobin is digested, the toxic metabolite hemozoin (a polarizable crystal) is formed and isolated in the parasite's food vacuole.

The intracellular parasites modify the erythrocyte in several ways. They derive energy from anaerobic glycolysis of glucose to lactic acid, which may contribute to clinical manifestations of hypoglycemia and lactic acidosis [2]. Parasites reduce red cell membrane deformability, resulting in hemolysis and accelerated splenic clearance, which may contribute to anemia. Alterations to uninfected red blood cells, such as the addition of P. falciparum glycosylphosphatidylinositol (GPI) to the membrane, may play a role in increased clearance of uninfected cells and contribute to anemia [3]. (See "Anemia in malaria".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jul 2016. | This topic last updated: Jul 28, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Cox-Singh J, Davis TM, Lee KS, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis 2008; 46:165.
  2. Daily JP, Scanfeld D, Pochet N, et al. Distinct physiological states of Plasmodium falciparum in malaria-infected patients. Nature 2007; 450:1091.
  3. Brattig NW, Kowalsky K, Liu X, et al. Plasmodium falciparum glycosylphosphatidylinositol toxin interacts with the membrane of non-parasitized red blood cells: a putative mechanism contributing to malaria anemia. Microbes Infect 2008; 10:885.
  4. Prato M, Giribaldi G, Polimeni M, et al. Phagocytosis of hemozoin enhances matrix metalloproteinase-9 activity and TNF-alpha production in human monocytes: role of matrix metalloproteinases in the pathogenesis of falciparum malaria. J Immunol 2005; 175:6436.
  5. Prato M, Gallo V, Giribaldi G, Arese P. Phagocytosis of haemozoin (malarial pigment) enhances metalloproteinase-9 activity in human adherent monocytes: role of IL-1beta and 15-HETE. Malar J 2008; 7:157.
  6. Ferreira A, Balla J, Jeney V, et al. A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med (Berl) 2008; 86:1097.
  7. Bedu-Addo G, Bates I. Causes of massive tropical splenomegaly in Ghana. Lancet 2002; 360:449.
  8. Wassmer SC, Taylor T, Maclennan CA, et al. Platelet-induced clumping of Plasmodium falciparum-infected erythrocytes from Malawian patients with cerebral malaria-possible modulation in vivo by thrombocytopenia. J Infect Dis 2008; 197:72.
  9. Wassmer SC, de Souza JB, Frère C, et al. TGF-beta1 released from activated platelets can induce TNF-stimulated human brain endothelium apoptosis: a new mechanism for microvascular lesion during cerebral malaria. J Immunol 2006; 176:1180.
  10. Wassmer SC, Combes V, Candal FJ, et al. Platelets potentiate brain endothelial alterations induced by Plasmodium falciparum. Infect Immun 2006; 74:645.
  11. Wassmer SC, Cianciolo GJ, Combes V, Grau GE. [LMP-420, a new therapeutic approach for cerebral malaria?]. Med Sci (Paris) 2006; 22:343.
  12. Joice R, Nilsson SK, Montgomery J, et al. Plasmodium falciparum transmission stages accumulate in the human bone marrow. Sci Transl Med 2014; 6:244re5.
  13. Imwong M, Snounou G, Pukrittayakamee S, et al. Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites. J Infect Dis 2007; 195:927.
  14. Volkman SK, Sabeti PC, DeCaprio D, et al. A genome-wide map of diversity in Plasmodium falciparum. Nat Genet 2007; 39:113.
  15. Jiang H, Yi M, Mu J, et al. Detection of genome-wide polymorphisms in the AT-rich Plasmodium falciparum genome using a high-density microarray. BMC Genomics 2008; 9:398.
  16. Mu J, Awadalla P, Duan J, et al. Recombination hotspots and population structure in Plasmodium falciparum. PLoS Biol 2005; 3:e335.
  17. Nair S, Miller B, Barends M, et al. Adaptive copy number evolution in malaria parasites. PLoS Genet 2008; 4:e1000243.
  18. Newbold C, Craig A, Kyes S, et al. Cytoadherence, pathogenesis and the infected red cell surface in Plasmodium falciparum. Int J Parasitol 1999; 29:927.
  19. Oh SS, Chishti AH, Palek J, Liu SC. Erythrocyte membrane alterations in Plasmodium falciparum malaria sequestration. Curr Opin Hematol 1997; 4:148.
  20. Aikawa M. Morphological changes in erythrocytes induced by malarial parasites. Biol Cell 1988; 64:173.
  21. Sharma YD. Knobs, knob proteins and cytoadherence in falciparum malaria. Int J Biochem 1991; 23:775.
  22. Sharma YD. Knob proteins in falciparum malaria. Indian J Med Res 1997; 106:53.
  23. Chookajorn T, Ponsuwanna P, Cui L. Mutually exclusive var gene expression in the malaria parasite: multiple layers of regulation. Trends Parasitol 2008; 24:455.
  24. Chaiyaroj SC, Angkasekwinai P, Buranakiti A, et al. Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: evidence for chondroitin sulfate a as a cytoadherence receptor. Am J Trop Med Hyg 1996; 55:76.
  25. Maubert B, Guilbert LJ, Deloron P. Cytoadherence of Plasmodium falciparum to intercellular adhesion molecule 1 and chondroitin-4-sulfate expressed by the syncytiotrophoblast in the human placenta. Infect Immun 1997; 65:1251.
  26. Rogerson SJ, Tembenu R, Dobaño C, et al. Cytoadherence characteristics of Plasmodium falciparum-infected erythrocytes from Malawian children with severe and uncomplicated malaria. Am J Trop Med Hyg 1999; 61:467.
  27. Maubert B, Fievet N, Tami G, et al. Cytoadherence of Plasmodium falciparum-infected erythrocytes in the human placenta. Parasite Immunol 2000; 22:191.
  28. Ponsford MJ, Medana IM, Prapansilp P, et al. Sequestration and microvascular congestion are associated with coma in human cerebral malaria. J Infect Dis 2012; 205:663.
  29. Das BS. Renal failure in malaria. J Vector Borne Dis 2008; 45:83.
  30. Chen Q, Schlichtherle M, Wahlgren M. Molecular aspects of severe malaria. Clin Microbiol Rev 2000; 13:439.
  31. Rowe JA, Moulds JM, Newbold CI, Miller LH. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature 1997; 388:292.
  32. Dondorp AM. Clinical significance of sequestration in adults with severe malaria. Transfus Clin Biol 2008; 15:56.
  33. Yeo TW, Lampah DA, Gitawati R, et al. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci U S A 2008; 105:17097.
  34. Taylor WR, Widjaja H, Basri H, et al. Changes in the total leukocyte and platelet counts in Papuan and non Papuan adults from northeast Papua infected with acute Plasmodium vivax or uncomplicated Plasmodium falciparum malaria. Malar J 2008; 7:259.
  35. Francischetti IM. Does activation of the blood coagulation cascade have a role in malaria pathogenesis? Trends Parasitol 2008; 24:258.
  36. Haldar K, Murphy SC, Milner DA, Taylor TE. Malaria: mechanisms of erythrocytic infection and pathological correlates of severe disease. Annu Rev Pathol 2007; 2:217.
  37. Janka JJ, Koita OA, Traoré B, et al. Increased pulmonary pressures and myocardial wall stress in children with severe malaria. J Infect Dis 2010; 202:791.
  38. Olszewski KL, Morrisey JM, Wilinski D, et al. Host-parasite interactions revealed by Plasmodium falciparum metabolomics. Cell Host Microbe 2009; 5:191.
  39. Weinberg JB, Lopansri BK, Mwaikambo E, Granger DL. Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria. Curr Opin Infect Dis 2008; 21:468.
  40. Yeo TW, Lampah DA, Gitawati R, et al. Recovery of endothelial function in severe falciparum malaria: relationship with improvement in plasma L-arginine and blood lactate concentrations. J Infect Dis 2008; 198:602.
  41. Miller LH, Mason SJ, Clyde DF, McGinniss MH. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N Engl J Med 1976; 295:302.
  42. Ryan JR, Stoute JA, Amon J, et al. Evidence for transmission of Plasmodium vivax among a duffy antigen negative population in Western Kenya. Am J Trop Med Hyg 2006; 75:575.
  43. Cavasini CE, Mattos LC, Couto AA, et al. Plasmodium vivax infection among Duffy antigen-negative individuals from the Brazilian Amazon region: an exception? Trans R Soc Trop Med Hyg 2007; 101:1042.
  44. Nagel RL, Fleming AF. Genetic epidemiology of the beta s gene. Baillieres Clin Haematol 1992; 5:331.
  45. Flint J, Harding RM, Clegg JB, Boyce AJ. Why are some genetic diseases common? Distinguishing selection from other processes by molecular analysis of globin gene variants. Hum Genet 1993; 91:91.
  46. Aidoo M, Terlouw DJ, Kolczak MS, et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 2002; 359:1311.
  47. Williams TN, Mwangi TW, Wambua S, et al. Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. J Infect Dis 2005; 192:178.
  48. Glikman D, Nguyen-Dinh P, Roberts JM, et al. Clinical malaria and sickle cell disease among multiple family members in Chicago, Illinois. Pediatrics 2007; 120:e745.
  49. Williams TN, Maitland K, Bennett S, et al. High incidence of malaria in alpha-thalassaemic children. Nature 1996; 383:522.
  50. Clegg JB, Weatherall DJ. Thalassemia and malaria: new insights into an old problem. Proc Assoc Am Physicians 1999; 111:278.
  51. Enevold A, Lusingu JP, Mmbando B, et al. Reduced risk of uncomplicated malaria episodes in children with alpha+-thalassemia in northeastern Tanzania. Am J Trop Med Hyg 2008; 78:714.
  52. Veenemans J, Andang'o PE, Mbugi EV, et al. Alpha+ -thalassemia protects against anemia associated with asymptomatic malaria: evidence from community-based surveys in Tanzania and Kenya. J Infect Dis 2008; 198:401.
  53. Pattanapanyasat K, Yongvanitchit K, Tongtawe P, et al. Impairment of Plasmodium falciparum growth in thalassemic red blood cells: further evidence by using biotin labeling and flow cytometry. Blood 1999; 93:3116.
  54. Pasvol G, Weatherall DJ, Wilson RJ, et al. Fetal haemoglobin and malaria. Lancet 1976; 1:1269.
  55. Gratzer WB, Dluzewski AR. The red blood cell and malaria parasite invasion. Semin Hematol 1993; 30:232.
  56. Genton B, al-Yaman F, Mgone CS, et al. Ovalocytosis and cerebral malaria. Nature 1995; 378:564.
  57. Boctor FN, Dorion RP. Malaria and hereditary elliptocytosis. Am J Hematol 2008; 83:753.
  58. Atkinson SH, Mwangi TW, Uyoga SM, et al. The haptoglobin 2-2 genotype is associated with a reduced incidence of Plasmodium falciparum malaria in children on the coast of Kenya. Clin Infect Dis 2007; 44:802.
  59. Ayi K, Min-Oo G, Serghides L, et al. Pyruvate kinase deficiency and malaria. N Engl J Med 2008; 358:1805.
  60. McGuire W, Knight JC, Hill AV, et al. Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. J Infect Dis 1999; 179:287.
  61. McGuire W, Hill AV, Allsopp CE, et al. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1994; 371:508.
  62. Dondorp AM, Lee SJ, Faiz MA, et al. The relationship between age and the manifestations of and mortality associated with severe malaria. Clin Infect Dis 2008; 47:151.
  63. Osier FH, Fegan G, Polley SD, et al. Breadth and magnitude of antibody responses to multiple Plasmodium falciparum merozoite antigens are associated with protection from clinical malaria. Infect Immun 2008; 76:2240.
  64. Doolan DL, Dobaño C, Baird JK. Acquired immunity to malaria. Clin Microbiol Rev 2009; 22:13.
  65. Schwarz NG, Adegnika AA, Breitling LP, et al. Placental malaria increases malaria risk in the first 30 months of life. Clin Infect Dis 2008; 47:1017.
  66. Mutabingwa TK, Bolla MC, Li JL, et al. Maternal malaria and gravidity interact to modify infant susceptibility to malaria. PLoS Med 2005; 2:e407.
  67. Mibei EK, Otieno WO, Orago AS, Stoute JA. Distinct pattern of class and subclass antibodies in immune complexes of children with cerebral malaria and severe malarial anaemia. Parasite Immunol 2008; 30:334.
  68. Leoratti FM, Durlacher RR, Lacerda MV, et al. Pattern of humoral immune response to Plasmodium falciparum blood stages in individuals presenting different clinical expressions of malaria. Malar J 2008; 7:186.
  69. D'Ombrain MC, Robinson LJ, Stanisic DI, et al. Association of early interferon-gamma production with immunity to clinical malaria: a longitudinal study among Papua New Guinean children. Clin Infect Dis 2008; 47:1380.