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Pathogenetic Immune Responses in Cerebral Malaria

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Malaria

Abstract

In this chapter we will critically review the body of evidence indicating that host immune responses to parasitic infection also play a critical role in cerebral malaria pathogenesis, in addition to parasite-induced pathology. First, in the field of innate immunity, we will discuss the ability of DAMPs and PAMPs to trigger pro-inflammatory responses. Moving on to adaptive immunity, we will underline the importance of the T cell dependency of the neurological syndrome, and will detail the molecules that have been shown essential in this pathogenetic mechanism. The involvement of antigen presenting cells (APC, including monocytes, dendritic cells and their subsets) will be reviewed, with a focus on malarial-associated immunosuppression. The potential importance of antigen processing, co-stimulation and cross-presentation in malarial pathology will also be highlighted. Finally, we will address the potential role of brain endothelial cells as APC and of membrane microparticles as amplifiers of pathology in cerebral malaria.

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References

  1. Engwerda CR, Good MF (2005) Interactions between malaria parasites and the host immune system. Curr Opin Immunol 17(4):381–387

    Article  CAS  PubMed  Google Scholar 

  2. Combes V et al (2010) Microvesiculation and cell interactions at the brain-endothelial interface in cerebral malaria pathogenesis. Prog Neurobiol 91(2):140–151

    Article  CAS  PubMed  Google Scholar 

  3. Grau GE, Hunt NH (2014) Cytokines and some of their effector mechanisms in cerebral malaria pathogenesis. In: Kremsner PG, Hommel M, Krishna S (eds) Encyclopedia of malaria. Springer, New York, pp 1–11

    Chapter  Google Scholar 

  4. Hunt NH, Grau GE (2003) Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria. Trends Immunol 24(9):491–499

    Article  CAS  PubMed  Google Scholar 

  5. Idro R, Marsh K, John CC, Newton CR (2010) Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res 68(4):267–274

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wassmer SC et al (2015) Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach. Am J Trop Med Hyg 93(3 Suppl):42–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Grau GE, Craig AG (2012) Cerebral malaria pathogenesis: revisiting parasite and host contributions. Future Microbiol 7:291–302

    Article  PubMed  Google Scholar 

  8. Combes V, De Souza JB, Renia L, Hunt NH, Grau GE (2005) Cerebral malaria: which parasite? Which model? Drug Discov Today Dis Models 2:141–148

    Article  CAS  Google Scholar 

  9. Hearn J, Rayment N, Landon DN, Katz DR, de Souza JB (2000) Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain microvasculature. Infect Immun 68(9):5364–5376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Coltel N, Combes V, Wassmer SC, Chimini G, Grau GE (2006) Cell vesiculation and immunopathology: implications in cerebral malaria. Microbes Infect 8(8):2305–2316

    Article  CAS  PubMed  Google Scholar 

  11. Schofield L, Grau GE (2005) Immunological processes in malaria pathogenesis. Nat Rev Immunol 5(9):722–735

    Article  CAS  PubMed  Google Scholar 

  12. Gazzinelli RT, Kalantari P, Fitzgerald KA, Golenbock DT (2014) Innate sensing of malaria parasites. Nat Rev Immunol 14(11):744–757

    Article  CAS  PubMed  Google Scholar 

  13. O’Neill LA, Golenbock D, Bowie AG (2013) The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 13(6):453–460

    Article  PubMed  Google Scholar 

  14. Franchi L, Warner N, Viani K, Nunez G (2009) Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev 227(1):106–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schofield L, Hackett F (1993) Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites. J Exp Med 177(1):145–153

    Article  CAS  PubMed  Google Scholar 

  16. Tachado SD et al (1996) Glycosylphosphatidylinositol toxin of Plasmodium induces nitric oxide synthase expression in macrophages and vascular endothelial cells by a protein tyrosine kinase-dependent and protein kinase C-dependent signaling pathway. J Immunol 156(5):1897–1907

    CAS  PubMed  Google Scholar 

  17. Shio MT et al (2009) Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog 5(8), e1000559

    Article  PubMed  Google Scholar 

  18. Dostert C et al (2009) Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One 4(8), e6510

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wassmer SC, Combes V, Grau GE (2003) Pathophysiology of cerebral malaria: role of host cells in the modulation of cytoadhesion. Ann N Y Acad Sci 992:30–38

    Article  CAS  PubMed  Google Scholar 

  20. Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12:991–1045

    Article  CAS  PubMed  Google Scholar 

  21. Gallego-Delgado J, Ty M, Orengo JM, van de Hoef D, Rodriguez A (2014) A surprising role for uric acid: the inflammatory malaria response. Curr Rheumatol Rep 16(2):401

    Article  PubMed  PubMed Central  Google Scholar 

  22. Jaiswal R, Grau GE, Bebawy M (2014) Cellular communication via microparticles: role in transfer of multidrug resistance in cancer. Future Oncol 10(4):655–669

    Article  CAS  PubMed  Google Scholar 

  23. Combes V et al (2004) Circulating endothelial microparticles in Malawian children with severe falciparum malaria complicated with coma. JAMA 291(21):2542–2544

    CAS  PubMed  Google Scholar 

  24. Pankoui Mfonkeu JB et al (2010) Elevated cell-specific microparticles are a biological marker for cerebral dysfunctions in human severe malaria. PLoS One 5(10), e13415

    Article  PubMed  PubMed Central  Google Scholar 

  25. Couper KN et al (2010) Parasite-derived plasma microparticles contribute significantly to malaria infection-induced inflammation through potent macrophage stimulation. PLoS Pathog 6(1), e1000744

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mantel PY, Marti M (2014) The role of extracellular vesicles in Plasmodium and other protozoan parasites. Cell Microbiol 16(3):344–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Figueiredo RT et al (2007) Characterization of heme as activator of Toll-like receptor 4. J Biol Chem 282(28):20221–20229

    Article  CAS  PubMed  Google Scholar 

  28. Belnoue E et al (2003) CCR5 deficiency decreases susceptibility to experimental cerebral malaria. Blood 101(11):4253–4259

    Article  CAS  PubMed  Google Scholar 

  29. Togbe D et al (2008) Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. PLoS One 3(7), e2608

    Article  PubMed  PubMed Central  Google Scholar 

  30. Nie CQ et al (2009) IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection. PLoS Pathog 5(4), e1000369

    Article  PubMed  PubMed Central  Google Scholar 

  31. Haque A et al (2011) Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria. J Immunol 186(11):6148–6156

    Article  CAS  PubMed  Google Scholar 

  32. Lau LS et al (2011) Blood-stage Plasmodium berghei infection generates a potent, specific CD8+ T-cell response despite residence largely in cells lacking MHC I processing machinery. J Infect Dis 204(12):1989–1996

    Article  CAS  PubMed  Google Scholar 

  33. Palomo J et al (2015) Critical role of IL-33 receptor ST2 in experimental cerebral malaria development. Eur J Immunol 45(5):1354–1365

    Article  CAS  PubMed  Google Scholar 

  34. Amante FH et al (2007) A role for natural regulatory T cells in the pathogenesis of experimental cerebral malaria. Am J Pathol 171(2):548–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Walther M et al (2009) Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog 5(4), e1000364

    Article  PubMed  PubMed Central  Google Scholar 

  36. Keswani T, Bhattacharyya A (2014) Differential role of T regulatory and Th17 in Swiss mice infected with Plasmodium berghei ANKA and Plasmodium yoelii. Exp Parasitol 141:82–92

    Article  CAS  PubMed  Google Scholar 

  37. Villegas-Mendez A et al (2012) IFN-gamma-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain. J Immunol 189(2):968–979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. McQuillan JA et al (2011) Coincident parasite and CD8 T cell sequestration is required for development of experimental cerebral malaria. Int J Parasitol 41(2):155–163

    Article  PubMed  Google Scholar 

  39. Shaw TN et al (2015) Perivascular arrest of CD8+ T cells is a signature of experimental cerebral malaria. PLoS Pathog 11(11), e1005210

    Article  PubMed  PubMed Central  Google Scholar 

  40. Newton CR, Taylor TE, Whitten RO (1998) Pathophysiology of fatal falciparum malaria in African children. Am J Trop Med Hyg 58(5):673–683

    CAS  PubMed  Google Scholar 

  41. Grau GE et al (1987) Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 237(4819):1210–1212

    Article  CAS  PubMed  Google Scholar 

  42. Artavanis-Tsakonas K, Tongren JE, Riley EM (2003) The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology. Clin Exp Immunol 133(2):145–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schmidt KE et al (2011) Induction of pro-inflammatory mediators in Plasmodium berghei infected BALB/c mice breaks blood-brain-barrier and leads to cerebral malaria in an IL-12 dependent manner. Microbes Infect 13(10):828–836

    Article  CAS  PubMed  Google Scholar 

  44. Barr M, Mc GI (1962) Diphtheria antitoxin levels in the serum of Gambian Africans. Trans R Soc Trop Med Hyg 56:368–370

    Article  CAS  PubMed  Google Scholar 

  45. Greenwood BM, Bradley-Moore AM, Bryceson AD, Palit A (1972) Immunosuppression in children with malaria. Lancet 1(7743):169–172

    Article  CAS  PubMed  Google Scholar 

  46. Chizzolini C, Grau GE, Geinoz A, Schrijvers D (1990) Lymphocyte-T interferon-gamma production induced by Plasmodium falciparum antigen is high in recently infected non-immune and low in immune subjects. Clin Exp Immunol 79:95–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ho M et al (1986) Antigen-specific immunosuppression in human malaria due to Plasmodium falciparum. J Infect Dis 153(4):763–771

    Article  CAS  PubMed  Google Scholar 

  48. Urban BC et al (1999) Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400(6739):73–77

    Article  CAS  PubMed  Google Scholar 

  49. Segura E, Villadangos JA (2009) Antigen presentation by dendritic cells in vivo. Curr Opin Immunol 21(1):105–110

    Article  CAS  PubMed  Google Scholar 

  50. Lundie RJ et al (2010) Blood-stage Plasmodium berghei infection leads to short-lived parasite-associated antigen presentation by dendritic cells. Eur J Immunol 40(6):1674–1681

    Article  CAS  PubMed  Google Scholar 

  51. Maglinao M, Klopfleisch R, Seeberger PH, Lepenies B (2013) The C-type lectin receptor DCIR is crucial for the development of experimental cerebral malaria. J Immunol 191(5):2551–2559

    Article  CAS  PubMed  Google Scholar 

  52. Schumak B et al (2015) Specific depletion of Ly6Chi inflammatory monocytes prevents immunopathology in experimental cerebral malaria. PLoS One 10(4), e0124080

    Article  PubMed  PubMed Central  Google Scholar 

  53. deWalick S et al (2007) Cutting edge: conventional dendritic cells are the critical APC required for the induction of experimental cerebral malaria. J Immunol 178(10):6033–6037

    Article  CAS  PubMed  Google Scholar 

  54. Sullivan RT et al (2016) B cell sub-types following acute malaria and associations with clinical immunity. Malar J 15(1):139

    Article  PubMed  PubMed Central  Google Scholar 

  55. Liu Y et al (2013) Role of IL-10-producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice. Eur J Immunol 43(11):2907–2918

    Article  CAS  PubMed  Google Scholar 

  56. Mintern JD, Villadangos JA (2015) Antigen-presenting cells look within during influenza infection. Nat Med 21(10):1123–1125

    Article  CAS  PubMed  Google Scholar 

  57. Sollid LM, Villadangos JA (2013) Antigen processing. Curr Opin Immunol 25(1):71–73

    Article  CAS  PubMed  Google Scholar 

  58. Mintern JD, Macri C, Villadangos JA (2015) Modulation of antigen presentation by intracellular trafficking. Curr Opin Immunol 34:16–21

    Article  CAS  PubMed  Google Scholar 

  59. Segura E, Albiston AL, Wicks IP, Chai SY, Villadangos JA (2009) Different cross-presentation pathways in steady-state and inflammatory dendritic cells. Proc Natl Acad Sci U S A 106(48):20377–20381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wilson NS et al (2006) Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat Immunol 7(2):165–172

    Article  CAS  PubMed  Google Scholar 

  61. Villadangos JA, Heath WR, Carbone FR (2007) Outside looking in: the inner workings of the cross-presentation pathway within dendritic cells. Trends Immunol 28(2):45–47

    Article  CAS  PubMed  Google Scholar 

  62. Wheway J, Obeid S, Couraud PO, Combes V, Grau GE (2013) The brain microvascular endothelium supports T cell proliferation and has potential for alloantigen presentation. PLoS One 8(1), e52586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lichtman AH (2007) Endothelial antigen presentation. In: Aird WC (ed) Endothelial biomedicine. Cambridge University Press, New York, pp 1098–1107

    Chapter  Google Scholar 

  64. Manes TD, Pober JS (2011) Identification of endothelial cell junctional proteins and lymphocyte receptors involved in transendothelial migration of human effector memory CD4+ T cells. J Immunol 186(3):1763–1768

    Article  CAS  PubMed  Google Scholar 

  65. Male DK, Pryce G, Hughes CC (1987) Antigen presentation in brain: MHC induction on brain endothelium and astrocytes compared. Immunology 60(3):453–459

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Becher B, Prat A, Antel JP (2000) Brain-immune connection: immuno-regulatory properties of CNS-resident cells. Glia 29(4):293–304

    Article  CAS  PubMed  Google Scholar 

  67. Engelhardt B (2008) The blood-central nervous system barriers actively control immune cell entry into the central nervous system. Curr Pharm Des 14(16):1555–1565

    Article  CAS  PubMed  Google Scholar 

  68. Engelhardt B (2008) Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines. J Neurol Sci 274(1-2):23–26

    Article  CAS  PubMed  Google Scholar 

  69. Hochman SE et al (2015) Fatal pediatric cerebral malaria is associated with intravascular monocytes and platelets that are increased with HIV coinfection. MBio 6(5), e01390-01315

    Article  Google Scholar 

  70. Razakandrainibe R, Pelleau S, Grau GE, Jambou R (2012) Antigen presentation by endothelial cells: what role in the pathophysiology of malaria? Trends Parasitol 28(4):151–160

    Article  CAS  PubMed  Google Scholar 

  71. Campanella GS et al (2006) Oligomerization of CXCL10 is necessary for endothelial cell presentation and in vivo activity. J Immunol 177(10):6991–6998

    Article  CAS  PubMed  Google Scholar 

  72. Campanella GS et al (2008) Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria. Proc Natl Acad Sci U S A 105(12):4814–4819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jambou R et al (2010) Plasmodium falciparum adhesion on human brain microvascular endothelial cells involves transmigration-like cup formation and induces opening of intercellular junctions. PLoS Pathog 6(7), e1001021

    Article  PubMed  PubMed Central  Google Scholar 

  74. Howland SW et al (2013) Brain microvessel cross-presentation is a hallmark of experimental cerebral malaria. EMBO Mol Med 5(7):916–931

    Article  CAS  PubMed Central  Google Scholar 

  75. Howland SW, Poh CM, Renia L (2015) Activated brain endothelial cells cross-present malaria antigen. PLoS Pathog 11(6), e1004963

    Article  PubMed  PubMed Central  Google Scholar 

  76. Ling ZL, Combes V, Grau GE, King NJ (2011) Microparticles as immune regulators in infectious disease—an opinion. Front Immunol 2:67

    Article  PubMed  PubMed Central  Google Scholar 

  77. Walters SB et al (2013) Microparticles from mycobacteria-infected macrophages promote inflammation and cellular migration. J Immunol 190(2):669–677

    Article  CAS  PubMed  Google Scholar 

  78. Wheway J, Latham SL, Combes V, Grau GE (2014) Endothelial microparticles interact with and support the proliferation of T cells. J Immunol 193(7):3378–3387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cockburn IA, Zavala F (2016) Dendritic cell function and antigen presentation in malaria. Curr Opin Immunol 40:1–6

    Article  CAS  PubMed  Google Scholar 

  80. Wassmer SC, Combes V, Grau GE (2011) Platelets and microparticles in cerebral malaria: the unusual suspects. Drug Discov Today Dis Mech 8:e15–e23

    Article  CAS  Google Scholar 

  81. Wassmer SC, Grau GE (2016) Platelets as pathogenetic effectors and killer cells in cerebral malaria. Expert Rev Hematol 9(6):515–517

    Article  CAS  PubMed  Google Scholar 

  82. El-Assaad F, Combes V, Grau GE (2014) Experimental models of microvascular immunopathology: the example of cerebral malaria. J Neuroinfect Dis 5(1):134

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Vascular Immunology Unit, Department of Pathology, School of Medical Sciences and Marie Bashir Institute, University of Sydney, Camperdown, NSW, Australia

    Georges Emile Raymond Grau & Samuel Crocodile Wassmer

  2. Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK

    Samuel Crocodile Wassmer

Authors
  1. Georges Emile Raymond Grau
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  2. Samuel Crocodile Wassmer
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Correspondence to Georges Emile Raymond Grau .

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Editors and Affiliations

  1. Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal

    Maria M. Mota

  2. Division of Parasitology, Department of Microbiology, New York University School of Medicine, New York, New York, USA

    Ana Rodriguez

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Grau, G.E.R., Wassmer, S.C. (2017). Pathogenetic Immune Responses in Cerebral Malaria. In: Mota, M., Rodriguez, A. (eds) Malaria. Springer, Cham. https://doi.org/10.1007/978-3-319-45210-4_4

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