Role of Complement in Immunity Against Malaria

  • José A. StouteEmail author


The role of complement in the immunity against malaria has been severely understudied. As a result, we know very little about this subject. Antibodies play an important role in suppressing parasitemia and could work by any or a combination of several mechanisms: inhibition of sporozoite invasion of hepatocytes, by blocking merozoite invasion of red blood cells (RBCs), by inducing phagocytosis of merozoites, or by inducing the phagocytosis of infected RBCs (IRBCs). Although there are some data that sporozoites are susceptible to complement activation, this seems to require high antibody levels. Complement can enhance the phagocytosis of IRBCs in the presence of nonimmune serum. In this system, natural antibodies that recognize altered native membrane antigens may play a role in activating complement, but there is also evidence of antibody-independent complement activation on the surface of IRBCs. The contribution of complement to anti-merozoite immunity was recently studied using filter-purified merozoites. C1q appeared to have a critical role in the inhibitory activity of anti-merozoite antibodies, but further studies are needed to confirm this and other contradictory observations reporting that antibody and complement can also enhance RBC invasion by merozoites. In vivo, cobra venom factor (CVF) has been used commonly in animal models to deplete complement. However, this approach is confounded by the fact that CVF is a complement activator that can promote indiscriminate deposition of C3b. Thus, CVF has produced contradictory results. Although there is now wide availability of genetically modified mice that are deficient in specific complement factors, relatively little work has been done with these animals. C1q−/− mice have been shown to have increased P. chabaudi parasitemia upon reinfection. On the other hand, C3−/− mice showed decreased P. berghei parasitemia. Much more work is needed before we have a clear picture of the role of complement in anti-malarial immunity. A better understanding of the role of complement in malaria immunity is needed if we are ever to develop a highly effective vaccine against malaria.


Antibody Complement Red blood cell Merozoite Malaria Sporozoite Immunity ADCI Phagocytosis C1q C3b 


  1. Arese P, Turrini F, Ginsburg H (1991) Erythrophagocytosis in malaria: host defence or menace to the macrophage? Parasitol Today 7(1):25–28CrossRefPubMedGoogle Scholar
  2. Atkinson JP, Glew RH, Neva FA, Frank MM (1975) Serum complement and immunity in experimental simian malaria. II. Preferential activation of early components and failure of depletion of late components to inhibit protective immunity. J Infect Dis 131(1):26–33CrossRefPubMedGoogle Scholar
  3. Ballou WR, Hoffman SL, Sherwood JA, Hollingdale MR, Neva FA, Hockmeyer WT, Gordon DM, Schneider I, Wirtz RA, Young JF, Reeve P, Chulay JD (1987) Safety and efficacy of a recombinant DNA Plasmodium falciparum sporozoite vaccine. Lancet 1(8545):1277–1281CrossRefPubMedGoogle Scholar
  4. Beeson JG, Drew DR, Boyle MJ, Feng G, Fowkes FJ, Richards JS (2016) Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria. FEMS Microbiol Rev 40(3):343–372CrossRefPubMedPubMedCentralGoogle Scholar
  5. Biryukov S, Stoute JA (2016) The use of filter-purified merozoites to assess anti-merozoite immunity. EBioMedicine 14:11–12CrossRefPubMedPubMedCentralGoogle Scholar
  6. Biryukov S, Angov E, Landmesser ME, Spring MD, Ockenhouse CF, Stoute JA (2016) Complement and antibody-mediated enhancement of red blood cell invasion and growth of malaria parasites. EBioMedicine 9:207–216CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bouharoun-Tayoun H, Attanath P, Sabchareon A, Chongsuphajaisiddhi T, Druilhe P (1990) Antibodies that protect humans against Plasmodium falciparum blood stages do not on their own inhibit parasite growth and invasion in vitro, but act in cooperation with monocytes. J Exp Med 172(6):1633–1641CrossRefPubMedGoogle Scholar
  8. Bouharoun-Tayoun H, Oeuvray C, Lunel F, Druilhe P (1995) Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages. J Exp Med 182(2):409–418CrossRefPubMedGoogle Scholar
  9. Boyle MJ, Reiling L, Feng G, Langer C, Osier FH, Aspeling-Jones H, Cheng YS, Stubbs J, Tetteh KK, Conway DJ, McCarthy JS, Muller I, Marsh K, Anders RF, Beeson JG (2015) Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria. Immunity 42(3):580–590CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bruce-Chwatt LJ (1956) Biometric study of spleen- and liver-weights in Africans and Europeans, with special reference to endemic malaria. Bull World Health Organ 15(3–5):513–548PubMedPubMedCentralGoogle Scholar
  11. Cavinato RA, Bastos KR, Sardinha LR, Elias RM, Alvarez JM, D’Imperio Lima MR (2001) Susceptibility of the different developmental stages of the asexual (schizogonic) erythrocyte cycle of Plasmodium chabaudi chabaudi to hyperimmune serum, immunoglobulin (Ig)G1, IgG2a and F(ab′)2 fragments. Parasite Immunol 23(11):587–597CrossRefPubMedGoogle Scholar
  12. Celada A, Cruchaud A, Perrin LH (1982) Opsonic activity of human immune serum on in vitro phagocytosis of Plasmodium falciparum infected red blood cells by monocytes. Clin Exp Immunol 47(3):635–644PubMedPubMedCentralGoogle Scholar
  13. Chapman WE, Ward PA (1977) Babesia rodhaini: requirement of complement for penetration of human erythrocytes. Science 196(4285):67–70CrossRefPubMedGoogle Scholar
  14. Coggeshall LT, Kumm HW (1937) Demonstration of passive immunity in experimental monkey malaria. J Exp Med 66(2):177–190CrossRefPubMedPubMedCentralGoogle Scholar
  15. Coggeshall LT, Kumm HW (1938) Effect of repeated superinfection upon the potency of immune serum of monkeys harboring chronic infections of plasmodium knowlesi. J Exp Med 68(1):17–27CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cohen S, Butcher GA (1970a) Properties of protective malarial antibody. Immunology 19(2):369–383PubMedPubMedCentralGoogle Scholar
  17. Cohen S, Butcher GA (1970b) Properties of protective malarial antibody. Nature 225(5234):732–734CrossRefPubMedGoogle Scholar
  18. Cohen S, McGregor IA, Carrington S (1961) Gamma-globulin and acquired immunity to human malaria. Nature 192:733–737CrossRefPubMedGoogle Scholar
  19. Cohen S, Butcher GA, Crandall RB (1969) Action of malarial antibody in vitro. Nature 223(5204):368–371CrossRefPubMedGoogle Scholar
  20. Cohen J, Nussenzweig V, Nussenzweig R, Vekemans J, Leach A (2010) From the circumsporozoite protein to the RTS, S/AS candidate vaccine. Hum Vaccin 6(1):90–96CrossRefPubMedGoogle Scholar
  21. Craig A, Scherf A (2001) Molecules on the surface of the Plasmodium falciparum infected erythrocyte and their role in malaria pathogenesis and immune evasion. Mol Biochem Parasitol 115(2):129–143CrossRefPubMedGoogle Scholar
  22. Dasari P, Heber SD, Beisele M, Torzewski M, Reifenberg K, Orning C, Fries A, Zapf AL, Baumeister S, Lingelbach K, Udomsangpetch R, Bhakdi SC, Reiss K, Bhakdi S (2012) Digestive vacuole of Plasmodium falciparum released during erythrocyte rupture dually activates complement and coagulation. Blood 119(18):4301–4310CrossRefPubMedGoogle Scholar
  23. Diggs CL, Osler AG (1969) Humoral immunity in rodent malaria. II. Inhibition of parasitemia by serum antibody. J Immunol 102(2):298–305PubMedGoogle Scholar
  24. Diggs CL, Osler AG (1975) Humoral immunity in rodent malaria. III: studies on the site of antibody action. J Immunol 114(4):1243–1247PubMedGoogle Scholar
  25. Eda S, Sherman IW (2002) Cytoadherence of malaria-infected red blood cells involves exposure of phosphatidylserine. Cell Physiol Biochem 12(5–6):373–384CrossRefPubMedGoogle Scholar
  26. Epstein N, Miller LH, Kaushel DC, Udeinya IJ, Rener J, Howard RJ, Asofsky R, Aikawa M, Hess RL (1981) Monoclonal antibodies against a specific surface determinant on malarial (Plasmodium knowlesi) merozoites block erythrocyte invasion. J Immunol 127(1):212–217PubMedGoogle Scholar
  27. Fadok VA, Warner ML, Bratton DL, Henson PM (1998) CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3). J Immunol 161(11):6250–6257PubMedGoogle Scholar
  28. Frevert U, Krzych U (2015) Plasmodium cellular effector mechanisms and the hepatic microenvironment. Front Microbiol 6:482PubMedPubMedCentralGoogle Scholar
  29. Frevert U, Engelmann S, Zougbede S, Stange J, Ng B, Matuschewski K, Liebes L, Yee H (2005) Intravital observation of Plasmodium berghei sporozoite infection of the liver. PLoS Biol 3(6):e192CrossRefPubMedPubMedCentralGoogle Scholar
  30. Greenberg ME, Sun M, Zhang R, Febbraio M, Silverstein R, Hazen SL (2006) Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J Exp Med 203(12):2613–2625CrossRefPubMedPubMedCentralGoogle Scholar
  31. Harnagel EE, Rhudy FV (1954) Falciparum malaria; report of a fatal case and autopsy findings. Calif Med 81(2):89–91PubMedPubMedCentralGoogle Scholar
  32. Harris JV, Bohr TM, Stracener C, Landmesser ME, Torres V, Mbugua A, Moratz C, Stoute JA (2012) Sequential Plasmodium chabaudi and Plasmodium berghei infections provide a novel model of severe malarial anemia. Infect Immun 80(9):2997–3007CrossRefPubMedPubMedCentralGoogle Scholar
  33. Herrington DA, Clyde DF, Losonsky G, Cortesia M, Murphy JR, Davis J, Baqar S, Felix AM, Heimer EP, Gillessen D, Nardin E, Nussenzweig RS, Hollingdale MR, Levin MM (1987) Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites. Nature 328(6127):257–259CrossRefPubMedGoogle Scholar
  34. Hollingdale MR, Sedegah M (2017) Development of whole sporozoite malaria vaccines. Expert Rev Vaccines 16(1):45–54CrossRefPubMedGoogle Scholar
  35. Hunter KW Jr, Winkelstein JA, Simpson TW (1979) Serum opsonic activity in rodent malaria: functional and immunochemical characteristics in vitro. J Immunol 123(6):2582–2587PubMedGoogle Scholar
  36. Jack RM, Ward PA (1980a) Babesia rodhaini interactions with complement: relationship to parasitic entry into red cells. J Immunol 124(4):1566–1573PubMedGoogle Scholar
  37. Jack RM, Ward PA (1980b) The role in vivo of C3 and the C3b receptor in babesial infection in the rat. J Immunol 124(4):1574–1578PubMedGoogle Scholar
  38. Jafarshad A, Dziegiel MH, Lundquist R, Nielsen LK, Singh S, Druilhe PL (2007) A novel antibody-dependent cellular cytotoxicity mechanism involved in defense against malaria requires costimulation of monocytes FcgammaRII and FcgammaRIII. J Immunol 178(5):3099–3106CrossRefPubMedGoogle Scholar
  39. Jarra W, Hills LA, March JC, Brown KN (1986) Protective immunity to malaria. Studies with cloned lines of Plasmodium chabaudi chabaudi and P. berghei in CBA/Ca mice. II. The effectiveness and inter- or intra-species specificity of the passive transfer of immunity with serum. Parasite Immunol 8(3):239–254CrossRefPubMedGoogle Scholar
  40. Kawamoto Y, Winger LA, Hong K, Matsuoka H, Chinzei Y, Kawamoto F, Kamimura K, Arakawa R, Sinden RE, Miyama A (1992) Plasmodium berghei: sporozoites are sensitive to human serum but not susceptible host serum. Exp Parasitol 75(3):361–368CrossRefPubMedGoogle Scholar
  41. Kennedy AT, Schmidt CQ, Thompson JK, Weiss GE, Taechalertpaisarn T, Gilson PR, Barlow PN, Crabb BS, Cowman AF, Tham WH (2015) Recruitment of factor H as a novel complement evasion strategy for blood-stage Plasmodium falciparum infection. J Immunol 196(3):1239–1248CrossRefPubMedGoogle Scholar
  42. Kennedy AT, Wijeyewickrema LC, Huglo A, Lin C, Pike R, Cowman AF, Tham WH (2017) Recruitment of human C1 esterase inhibitor controls complement activation on blood stage Plasmodium falciparum merozoites. J Immunol 198(12):4728–4737CrossRefPubMedGoogle Scholar
  43. Khusmith S, Druilhe P (1982) Specific arming of monocytes by cytophilic IgG promotes Plasmodium falciparum merozoite ingestion. Trans R Soc Trop Med Hyg 76(3):423–424CrossRefPubMedGoogle Scholar
  44. Khusmith S, Druilhe P (1983a) Antibody-dependent ingestion of P. falciparum merozoites by human blood monocytes. Parasite Immunol 5(4):357–368CrossRefPubMedGoogle Scholar
  45. Khusmith S, Druilhe P (1983b) Cooperation between antibodies and monocytes that inhibit in vitro proliferation of Plasmodium falciparum. Infect Immun 41(1):219–223PubMedPubMedCentralGoogle Scholar
  46. Khusmith S, Druilhe P, Gentilini M (1982) Enhanced Plasmodium falciparum merozoite phagocytosis by monocytes from immune individuals. Infect Immun 35(3):874–879PubMedPubMedCentralGoogle Scholar
  47. Krishnan V, Ponnuraj K, Xu Y, Macon K, Volanakis JE, Narayana SV (2009) The crystal structure of cobra venom factor, a cofactor for C3- and C5-convertase CVFBb. Structure 17(4):611–619CrossRefPubMedPubMedCentralGoogle Scholar
  48. Kumaratilake LM, Ferrante A (2000) Opsonization and phagocytosis of Plasmodium falciparum merozoites measured by flow cytometry. Clin Diagn Lab Immunol 7(1):9–13PubMedPubMedCentralGoogle Scholar
  49. Long CA, Daly TM, Kima P, Srivastava I (1994) Immunity to erythrocytic stages of malarial parasites. Am J Trop Med Hyg 50(4 Suppl):27–32CrossRefPubMedGoogle Scholar
  50. Majarian WR, Daly TM, Weidanz WP, Long CA (1984) Passive immunization against murine malaria with an IgG3 monoclonal antibody. J Immunol 132(6):3131–3137PubMedGoogle Scholar
  51. McCoy ME, Golden HE, Doll TA, Yang Y, Kaba SA, Zou X, Gerbasi VR, Burkhard P, Lanar DE (2013) Mechanisms of protective immune responses induced by the Plasmodium falciparum circumsporozoite protein-based, self-assembling protein nanoparticle vaccine. Malar J 12:136CrossRefPubMedPubMedCentralGoogle Scholar
  52. McGilvray ID, Serghides L, Kapus A, Rotstein OD, Kain KC (2000) Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood 96(9):3231–3240PubMedGoogle Scholar
  53. McGregor IA (1964) The passive transfer of human malarial immunity. Am J Trop Med Hyg 13:237–239CrossRefGoogle Scholar
  54. Miller LH, Aikawa M, Dvorak JA (1975) Malaria (Plasmodium knowlesi) merozoites: immunity and the surface coat. J Immunol 114(4):1237–1242PubMedGoogle Scholar
  55. Miller LH, David PH, Hudson DE, Hadley TJ, Richards RL, Aikawa M (1984) Monoclonal antibodies to a 140,000-m.w. protein on Plasmodium knowlesi merozoites inhibit their invasion of rhesus erythrocytes. J Immunol 132(1):438–442PubMedGoogle Scholar
  56. Packer BJ, Kreier JP (1986) Plasmodium berghei malaria: effects of acute-phase serum and erythrocyte-bound immunoglobulins on erythrophagocytosis by rat peritoneal macrophages. Infect Immun 51(1):141–146PubMedPubMedCentralGoogle Scholar
  57. Patel SN, Serghides L, Smith TG, Febbraio M, Silverstein RL, Kurtz TW, Pravenec M, Kain KC (2004) CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages. J Infect Dis 189(2):204–213CrossRefPubMedGoogle Scholar
  58. Quinn TC, Wyler DJ (1979) Mechanisms of action of hyperimmune serum in mediating protective immunity to rodent malaria (Plasmodium berghei). J Immunol 123(5):2245–2249PubMedGoogle Scholar
  59. Ramos TN, Bullard DC, Barnum SR (2012) Deletion of the complement phagocytic receptors CR3 and CR4 does not alter susceptibility to experimental cerebral malaria. Parasite Immunol 34(11):547–550CrossRefPubMedPubMedCentralGoogle Scholar
  60. Renia L, Goh YS (2016) Malaria parasites: the great escape. Front Immunol 7:463CrossRefPubMedPubMedCentralGoogle Scholar
  61. Rosa TF, Flammersfeld A, Ngwa CJ, Kiesow M, Fischer R, Zipfel PF, Skerka C, Pradel G (2015) The Plasmodium falciparum blood stages acquire factor H family proteins to evade destruction by human complement. Cell Microbiol 18(4):573–590CrossRefPubMedPubMedCentralGoogle Scholar
  62. Sabchareon A, Burnouf T, Ouattara D, Attanath P, Bouharoun-Tayoun H, Chantavanich P, Foucault C, Chongsuphajaisiddhi T, Druilhe P (1991) Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria. Am J Trop Med Hyg 45(3):297–308CrossRefPubMedGoogle Scholar
  63. Sam-Yellowe TY, Judd RC (1990) Passive immunization against Plasmodium chabaudi malaria with Pch 21 merozoite monoclonal antibody. Parasitol Res 76(5):457–460CrossRefPubMedGoogle Scholar
  64. Schetters TP, Van LP, Van Zon AA, Eling WM (1985) Interactions of Plasmodium berghei-infected erythrocytes with complement. J Protozool 32(2):321–325CrossRefPubMedGoogle Scholar
  65. Seinen W, Stegmann T, Kuil H (1982) Complement does not play a role in promoting Babesia rodhaini infections in Balb/C mice. Z Parasitenkd 68(3):249–257CrossRefPubMedGoogle Scholar
  66. Shear HL, Nussenzweig RS, Bianco C (1979) Immune phagocytosis in murine malaria. J Exp Med 149(6):1288–1298CrossRefPubMedGoogle Scholar
  67. Shin SC, Vanderberg JP, Terzakis JA (1982) Direct infection of hepatocytes by sporozoites of Plasmodium berghei. J Protozool 29(3):448–454CrossRefPubMedGoogle Scholar
  68. Spencer Valero LM, Ogun SA, Fleck SL, Ling IT, Scott-Finnigan TJ, Blackman MJ, Holder AA (1998) Passive immunization with antibodies against three distinct epitopes on Plasmodium yoelii merozoite surface protein 1 suppresses parasitemia. Infect Immun 66(8):3925–3930PubMedPubMedCentralGoogle Scholar
  69. Spencer AJ, Longley RJ, Gola A, Ulaszewska M, Lambe T, Hill AV (2017) The threshold of protection from liver-stage malaria relies on a fine balance between the number of infected hepatocytes and effector CD8+ T cells present in the liver. J Immunol 198(5):2006–2016CrossRefPubMedPubMedCentralGoogle Scholar
  70. Stanley HA, Mayes JT, Cooper NR, Reese RT (1984) Complement activation by the surface of Plasmodium falciparum infected erythrocytes. Mol Immunol 21(2):145–150CrossRefPubMedGoogle Scholar
  71. Stevenson MM, Kraal G (1989) Histological changes in the spleen and liver of C57BL/6 and A/J mice during Plasmodium chabaudi AS infection. Exp Mol Pathol 51(1):80–95CrossRefPubMedGoogle Scholar
  72. Stoute JA, Slaoui M, Heppner DG, Momin P, Kester KE, Desmons P, Wellde BT, Garcon N, Krzych U, Marchand M (1997) A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group. N Engl J Med 336(2):86–91CrossRefPubMedGoogle Scholar
  73. Taylor PR, Seixas E, Walport MJ, Langhorne J, Botto M (2001) Complement contributes to protective immunity against reinfection by Plasmodium chabaudi chabaudi parasites. Infect Immun 69(6):3853–3859CrossRefPubMedPubMedCentralGoogle Scholar
  74. Tosta CE, Wedderburn N (1980) Immune phagocytosis of Plasmodium yoelii-infected erythrocytes by macrophages and eosinophils. Clin Exp Immunol 42(1):114–120PubMedPubMedCentralGoogle Scholar
  75. Touray MG, Seeley DC Jr, Miller LH (1994) Plasmodium gallinaceum: differential lysis of two developmental stages of malaria sporozoites by the alternative pathway of complement. Exp Parasitol 78(3):294–301CrossRefPubMedGoogle Scholar
  76. Turrini F, Ginsburg H, Bussolino F, Pescarmona GP, Serra MV, Arese P (1992) Phagocytosis of Plasmodium falciparum-infected human red blood cells by human monocytes: involvement of immune and nonimmune determinants and dependence on parasite developmental stage. Blood 80(3):801–808PubMedGoogle Scholar
  77. Turrini F, Giribaldi G, Carta F, Mannu F, Arese P (2003) Mechanisms of band 3 oxidation and clustering in the phagocytosis of Plasmodium falciparum-infected erythrocytes. Redox Rep 8(5):300–303CrossRefPubMedGoogle Scholar
  78. Ward PA, Sterzel RB, Lucia HL, Campbell GH, Jack RM (1981) Complement does not facilitate plasmodial infections. J Immunol 126(5):1826–1828PubMedGoogle Scholar
  79. Weiss WR, Jiang CG (2012) Protective CD8+ T lymphocytes in primates immunized with malaria sporozoites. PLoS One 7(2):e31247CrossRefPubMedPubMedCentralGoogle Scholar
  80. White MT, Bejon P, Olotu A, Griffin JT, Riley EM, Kester KE, Ockenhouse CF, Ghani AC (2013) The relationship between RTS,S vaccine-induced antibodies, CD4(+) T cell responses and protection against Plasmodium falciparum infection. PLoS One 8(4):e61395CrossRefPubMedPubMedCentralGoogle Scholar
  81. Whitten R, Milner DA Jr, Yeh MM, Kamiza S, Molyneux ME, Taylor TE (2011) Liver pathology in Malawian children with fatal encephalopathy. Hum Pathol 42(9):1230–1239CrossRefPubMedPubMedCentralGoogle Scholar
  82. Yahata K, Treeck M, Culleton R, Gilberger TW, Kaneko O (2012) Time-lapse imaging of red blood cell invasion by the rodent malaria parasite Plasmodium yoelii. PLoS One 7(12):e50780CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Medicine, and Microbiology and ImmunologyPenn State University College of MedicineHersheyUSA

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