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Cerebral Malaria

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Neuroinflammation and Neurodegeneration

Abstract

Cerebral malaria (CM), defined as the presence of P. falciparum asexual stages on peripheral blood smear in a person with coma and no other cause for encephalopathy, is estimated to affect more than 800,000 people a year and has a 15–20 % mortality rate. CM predominantly affects children <5 years of age in Africa, but in Southeast Asia it is more common in adolescents and adults. Approximately 25 % of African children with CM develop long-term cognitive impairment. The pathogenesis of cerebral malaria appears to involve several components. The primary factor in pathogenesis of CM is thought to be sequestration, a blockage of microcirculatory vessels in the brain by parasitized red blood cells, along with lesser numbers of leukocytes and platelets. Other factors that appear to be involved in pathogenesis include systemic and central nervous system (CNS) production of proinflammatory cytokines and chemokines, including tumor necrosis factor, interferon-γ, and RANTES; release of free heme during hemolysis; endothelial activation leading to blood–brain barrier breakdown; CNS nitric oxide production; and genetic polymorphisms (e.g., sickle cell trait) that alter these responses or protect in other ways from severe disease. Murine models of cerebral malaria have provided new insights into the disease, but the difference in the parasite species and the host response has limited translation of findings from murine models into human CM studies. Nonhuman primate models are closer to human disease, but are limited by cost and ethical concerns. Therapies currently being studied for adjunctive therapy in CM include arginine (a donor of nitric oxide), inhaled nitric oxide, and recombinant erythropoietin. The potential benefits and harm of each therapy require close study, as many areas of CM pathogenesis remain unclear. Further studies are required, particularly in human disease, to better understand pathogenesis so that effective adjunctive therapy for this illness can be developed.

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Abbreviations

ANG1:

Angiopoietin-1

ANG2:

Angiopoietin-2

BBB:

Blood–brain barrier

CM:

Cerebral malaria

CNS:

Central nervous system

CSF:

Cerebral spinal fluid

EC:

Endothelial cell

ECM:

Experimental cerebral malaria

EDHF:

Endothelium-derived hyperpolarization factor

EPO:

Erythropoietin

ET-1:

Endothelin-1

G6PD:

Glucose-6-phosphate dehydrogenase

GPI:

Glycosylphosphatidylinositol

HO:

Heme oxygenase

ICAM-1:

Intercellular adhesion molecule-1

iNOS:

Inducible nitric oxide synthase

LT:

Lymphotoxin

MT:

Metallothionein

NK:

Natural killer

NO:

Nitric oxide

P:

Plasmodium

PfEMP-1:

P. falciparum erythrocyte membrane protein-1

pRBC:

Parasitized red blood cell

SNP:

Single nucleotide polymorphisms

TLR:

Toll-like receptor

VCAM-1:

Vascular cell-adhesion molecule-1

VWF:

von Willebrand factor

WHO:

World Health Organization

References

  1. WHO. World malaria report 2012. Geneva, Switzerland: World Health Organization; 2012.

    Google Scholar 

  2. Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, et al. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet. 2012;379(9814): 413–31. PubMed PMID: 22305225.

    PubMed  Google Scholar 

  3. Hien TT, Day NPJ, Phu NH, Mai NTH, Chau TTH, Loc PP, et al. A controlled trial of Artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med. 1996;335(2):76–83. PubMed PMID: 8649493.

    CAS  Google Scholar 

  4. WHO. Severe falciparum malaria. World Health Organization, communicable diseases cluster. Trans R Soc Trop Med Hyg. 2000;94 Suppl 1:S1–90. PubMed PMID: 11103309.

    Google Scholar 

  5. Newton CR, Krishna S. Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol Ther. 1998;79(1):1–53. PubMed PMID: 9719344.

    CAS  PubMed  Google Scholar 

  6. John CC, Panoskaltsis-Mortari A, Opoka RO, Park GS, Orchard PJ, Jurek AM, et al. Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg. 2008;78(2):198–205. PubMed PMID: 18256412.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol. 2005;4(12):827–40. PubMed PMID: 16297841.

    PubMed  Google Scholar 

  8. Idro R, Kakooza-Mwesige A, Balyejjussa S, Mirembe G, Mugasha C, Tugumisirize J, et al. Severe neurological sequelae and behaviour problems after cerebral malaria in Ugandan children. BMC Res Notes. 2010;3:104. PubMed PMID: 20398391, Pubmed Central PMCID: 2861066.

    PubMed Central  PubMed  Google Scholar 

  9. Idro R, Marsh K, John CC, Newton CR. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res. 2010;68(4):267–74. PubMed PMID: 20606600, Pubmed Central PMCID: 3056312.

    PubMed Central  PubMed  Google Scholar 

  10. Boivin MJ, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, et al. Cognitive impairment after cerebral malaria in children: a prospective study. Pediatrics. 2007;119(2):e360–6. PubMed PMID: 17224457, Pubmed Central PMCID: 2743741.

    PubMed Central  PubMed  Google Scholar 

  11. Newton CR, Warrell DA. Neurological manifestations of falciparum malaria. Ann Neurol. 1998;43(6):695–702. PubMed PMID: 9629838.

    CAS  PubMed  Google Scholar 

  12. Haldar K, Murphy SC, Milner DA, Taylor TE. Malaria: mechanisms of erythrocytic infection and pathological correlates of severe disease. Annu Rev Pathol. 2007;2:217–49. PubMed PMID: 18039099.

    CAS  PubMed  Google Scholar 

  13. Berendt AR, Ferguson DJ, Gardner J, Turner G, Rowe A, McCormick C, et al. Molecular mechanisms of sequestration in malaria. Parasitology. 1994;108(Suppl):S19–28. PubMed PMID: 8084651.

    PubMed  Google Scholar 

  14. Patnaik JK, Das BS, Mishra SK, Mohanty S, Satpathy SK, Mohanty D. Vascular clogging, mononuclear cell margination, and enhanced vascular permeability in the pathogenesis of human cerebral malaria. Am J Trop Med Hyg. 1994;51(5):642–7. PubMed PMID: 7985757.

    CAS  PubMed  Google Scholar 

  15. Grau GE, Mackenzie CD, Carr RA, Redard M, Pizzolato G, Allasia C, et al. Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria. J Infect Dis. 2003;187(3):461–6. PubMed PMID: 12552430.

    PubMed  Google Scholar 

  16. Ponsford MJ, Medana IM, Prapansilp P, Hien TT, Lee SJ, Dondorp AM, et al. Sequestration and microvascular congestion are associated with coma in human cerebral malaria. J Infect Dis. 2012;205(4):663–71. PubMed PMID: 22207648, Pubmed Central PMCID: 3266137.

    PubMed Central  PubMed  Google Scholar 

  17. Medana IM, Day NP, Hien TT, Mai NT, Bethell D, Phu NH, et al. Axonal injury in cerebral malaria. Am J Pathol. 2002;160(2):655–66. PubMed PMID: 11839586, Pubmed Central PMCID: 1850649.

    PubMed Central  PubMed  Google Scholar 

  18. Cooke BM, Morris-Jones S, Greenwood BM, Nash GB. Mechanisms of cytoadhesion of flowing, parasitized red blood cells from Gambian children with falciparum malaria. Am J Trop Med Hyg. 1995;53(1):29–35. PubMed PMID: 7542844.

    CAS  PubMed  Google Scholar 

  19. Newbold C, Warn P, Black G, Berendt A, Craig A, Snow B, et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am J Trop Med Hyg. 1997;57(4):389–98. PubMed PMID: 9347951.

    CAS  PubMed  Google Scholar 

  20. Chakravorty SJ, Hughes KR, Craig AG. Host response to cytoadherence in Plasmodium falciparum. Biochem Soc Trans. 2008;36(Pt 2):221–8. PubMed PMID: 18363564.

    CAS  PubMed  Google Scholar 

  21. Park GS, Ireland KF, Opoka RO, John CC. Evidence of endothelial activation in asymptomatic plasmodium falciparum parasitemia and effect of blood group on levels of von Willebrand factor in malaria. J Pediatr Infect Dis Soc. 2012;1(1):16–25.

    Google Scholar 

  22. van der Heyde HC, Nolan J, Combes V, Gramaglia I, Grau GE. A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol. 2006;22(11):503–8. PubMed PMID: 16979941.

    PubMed  Google Scholar 

  23. Handunnetti SM, David PH, Perera KL, Mendis KN. Uninfected erythrocytes form “rosettes” around Plasmodium falciparum infected erythrocytes. Am J Trop Med Hyg. 1989;40(2): 115–8. PubMed PMID: 2645800.

    CAS  PubMed  Google Scholar 

  24. Pain A, Ferguson DJ, Kai O, Urban BC, Lowe B, Marsh K, et al. Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. Proc Natl Acad Sci U S A. 2001;98(4):1805–10. PubMed PMID: 11172032, Pubmed Central PMCID: 29338.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Chotivanich K, Sritabal J, Udomsangpetch R, Newton P, Stepniewska KA, Ruangveerayuth R, et al. Platelet-induced autoagglutination of Plasmodium falciparum-infected red blood cells and disease severity in Thailand. J Infect Dis. 2004;189(6):1052–5. PubMed PMID: 14999609.

    PubMed  Google Scholar 

  26. Cooke BM, Mohandas N, Coppel RL. Malaria and the red blood cell membrane. Semin Hematol. 2004;41(2):173–88. PubMed PMID: 15071793.

    PubMed  Google Scholar 

  27. Ahlqvist J. Decreased red cell deformability and vascular obstruction in falciparum malaria illustrated by a fatal case. Scand J Haematol. 1985;35(5):531–5. PubMed PMID: 3911374.

    CAS  PubMed  Google Scholar 

  28. Bridges DJ, Bunn J, van Mourik JA, Grau G, Preston RJ, Molyneux M, et al. Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings. Blood. 2010;115(7):1472–4. PubMed PMID: 19897581, Pubmed Central PMCID: 2840836.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10(3):165–77. PubMed PMID: 19234476.

    CAS  PubMed  Google Scholar 

  30. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006;12(2):235–9. PubMed PMID: 16462802.

    CAS  PubMed  Google Scholar 

  31. Andresen J, Shafi NI, Bryan Jr RM. Endothelial influences on cerebrovascular tone. J Appl Physiol. 2006;100(1):318–27. PubMed PMID: 16357085.

    CAS  PubMed  Google Scholar 

  32. Toure FS, Ouwe-Missi-Oukem-Boyer O, Bisvigou U, Moussa O, Rogier C, Pino P, et al. Apoptosis: a potential triggering mechanism of neurological manifestation in Plasmodium falciparum malaria. Parasite Immunol. 2008;30(1):47–51. PubMed PMID: 18086016.

    CAS  PubMed  Google Scholar 

  33. Maier AG, Rug M, O’Neill MT, Brown M, Chakravorty S, Szestak T, et al. Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell. 2008;134(1):48–61. PubMed PMID: 18614010, Pubmed Central PMCID: 2568870.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Maier AG, Cooke BM, Cowman AF, Tilley L. Malaria parasite proteins that remodel the host erythrocyte. Nat Rev Microbiol. 2009;7(5):341–54. PubMed PMID: 19369950.

    CAS  PubMed  Google Scholar 

  35. Mishra SK, Wiese L. Advances in the management of cerebral malaria in adults. Curr Opin Neurol. 2009;22(3):302–7. PubMed PMID: 19434799.

    PubMed  Google Scholar 

  36. de Souza JB, Hafalla JC, Riley EM, Couper KN. Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease. Parasitology. 2010;137(5):755–72. PubMed PMID: 20028608.

    PubMed  Google Scholar 

  37. Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med. 2004;10(2):143–5. PubMed PMID: 14745442.

    CAS  PubMed  Google Scholar 

  38. Seydel KB, Milner Jr DA, Kamiza SB, Molyneux ME, Taylor TE. The distribution and intensity of parasite sequestration in comatose Malawian children. J Infect Dis. 2006;194(2):208–15. PubMed PMID: 16779727, Pubmed Central PMCID: 1515074.

    PubMed Central  PubMed  Google Scholar 

  39. Looareesuwan S, Wilairatana P, Krishna S, Kendall B, Vannaphan S, Viravan C, et al. Magnetic resonance imaging of the brain in patients with cerebral malaria. Clin Infect Dis. 1995;21(2):300–9. PubMed PMID: 8562735.

    CAS  PubMed  Google Scholar 

  40. White NJ. Lumbar puncture in cerebral malaria. Lancet. 1991;338(8767):640–1. PubMed PMID: 1679182.

    CAS  PubMed  Google Scholar 

  41. Langhorne J, Buffet P, Galinski M, Good M, Harty J, Leroy D, et al. The relevance of non-human primate and rodent malaria models for humans. Malar J. 2011;10(1):23. PubMed PMID: 21288352, Pubmed Central PMCID: 3041720.

    PubMed Central  PubMed  Google Scholar 

  42. Curfs JH, Schetters TP, Hermsen CC, Jerusalem CR, van Zon AA, Eling WM. Immunological aspects of cerebral lesions in murine malaria. Clin Exp Immunol. 1989;75(1):136–40. PubMed PMID: 2649283, Pubmed Central PMCID: 1541862.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Schofield L, Grau GE. Immunological processes in malaria pathogenesis. Nat Rev Immunol. 2005;5(9):722–35. PubMed PMID: 16138104.

    CAS  PubMed  Google Scholar 

  44. Mitchell AJ, Hansen AM, Hee L, Ball HJ, Potter SM, Walker JC, et al. Early cytokine production is associated with protection from murine cerebral malaria. Infect Immun. 2005;73(9):5645–53. PubMed PMID: 16113282, Pubmed Central PMCID: 1231146.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Curfs JH, van der Meide PH, Billiau A, Meuwissen JH, Eling WM. Plasmodium berghei: recombinant interferon-gamma and the development of parasitemia and cerebral lesions in malaria-infected mice. Exp Parasitol. 1993;77(2):212–23. PubMed PMID: 8375490.

    CAS  PubMed  Google Scholar 

  46. White NJ, Turner GD, Medana IM, Dondorp AM, Day NP. The murine cerebral malaria phenomenon. Trends Parasitol. 2010;26(1):11–5. PubMed PMID: 19932638, Pubmed Central PMCID: 2807032.

    PubMed Central  PubMed  Google Scholar 

  47. Engwerda C, Belnoue E, Gruner AC, Renia L. Experimental models of cerebral malaria. Curr Top Microbiol Immunol. 2005;297:103–43. PubMed PMID: 16265904.

    CAS  PubMed  Google Scholar 

  48. de Souza JB, Riley EM. Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis. Microbes Infect. 2002;4(3):291–300. PubMed PMID: 11909739.

    PubMed  Google Scholar 

  49. Belnoue E, Kayibanda M, Vigario AM, Deschemin JC, van Rooijen N, Viguier M, et al. On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria. J Immunol. 2002;169(11):6369–75. PubMed PMID: 12444144.

    CAS  PubMed  Google Scholar 

  50. Lou J, Lucas R, Grau GE. Pathogenesis of cerebral malaria: recent experimental data and possible applications for humans. Clin Microbiol Rev. 2001;14(4):810–20. Table of contents, PubMed PMID: 11585786, Pubmed Central PMCID: 89004.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Ma N, Hunt NH, Madigan MC, Chan-Ling T. Correlation between enhanced vascular permeability, up-regulation of cellular adhesion molecules and monocyte adhesion to the endothelium in the retina during the development of fatal murine cerebral malaria. Am J Pathol. 1996;149(5):1745–62. PubMed PMID: 8909263, Pubmed Central PMCID: 1865264.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Hansen DS, Bernard NJ, Nie CQ, Schofield L. NK cells stimulate recruitment of CXCR3+ T cells to the brain during Plasmodium berghei-mediated cerebral malaria. J Immunol. 2007;178(9):5779–88. PubMed PMID: 17442962.

    CAS  PubMed  Google Scholar 

  53. Belnoue E, Potter SM, Rosa DS, Mauduit M, Gruner AC, Kayibanda M, et al. Control of pathogenic CD8+ T cell migration to the brain by IFN-gamma during experimental cerebral malaria. Parasite Immunol. 2008;30(10):544–53. PubMed PMID: 18665903.

    CAS  PubMed  Google Scholar 

  54. Hansen DS, Siomos MA, Buckingham L, Scalzo AA, Schofield L. Regulation of murine cerebral malaria pathogenesis by CD1d-restricted NKT cells and the natural killer complex. Immunity. 2003;18(3):391–402. PubMed PMID: 12648456.

    CAS  PubMed  Google Scholar 

  55. Renia L, Potter SM, Mauduit M, Rosa DS, Kayibanda M, Deschemin JC, et al. Pathogenic T cells in cerebral malaria. Int J Parasitol. 2006;36(5):547–54. PubMed PMID: 16600241.

    CAS  PubMed  Google Scholar 

  56. Yanez DM, Manning DD, Cooley AJ, Weidanz WP, van der Heyde HC. Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria. J Immunol. 1996;157(4):1620–4. PubMed PMID: 8759747.

    CAS  PubMed  Google Scholar 

  57. Yanez DM, Batchelder J, van der Heyde HC, Manning DD, Weidanz WP. Gamma delta T-cell function in pathogenesis of cerebral malaria in mice infected with Plasmodium berghei ANKA. Infect Immun. 1999;67(1):446–8. PubMed PMID: 9864254, Pubmed Central PMCID: 96335.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Grau GE, Heremans H, Piguet PF, Pointaire P, Lambert PH, Billiau A, et al. Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor. Proc Natl Acad Sci U S A. 1989; 86(14):5572–4. PubMed PMID: 2501793, Pubmed Central PMCID: 297664.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Hanum PS, Hayano M, Kojima S. Cytokine and chemokine responses in a cerebral malaria-susceptible or -resistant strain of mice to Plasmodium berghei ANKA infection: early chemokine expression in the brain. Int Immunol. 2003;15(5):633–40. PubMed PMID: 12697663.

    Google Scholar 

  60. Engwerda CR, Mynott TL, Sawhney S, De Souza JB, Bickle QD, Kaye PM. Locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principle mediator of murine cerebral malaria. J Exp Med. 2002;195(10):1371–7. PubMed PMID: 12021316, Pubmed Central PMCID: 2193758.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Lucas R, Lou JN, Juillard P, Moore M, Bluethmann H, Grau GE. Respective role of TNF receptors in the development of experimental cerebral malaria. J Neuroimmunol. 1997;72(2):143–8. PubMed PMID: 9042106.

    PubMed  Google Scholar 

  62. Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science. 1987;237(4819):1210–2. PubMed PMID: 3306918.

    CAS  PubMed  Google Scholar 

  63. Wiese L, Kurtzhals JA, Penkowa M. Neuronal apoptosis, metallothionein expression and proinflammatory responses during cerebral malaria in mice. Exp Neurol. 2006;200(1):216–26. PubMed PMID: 16624296.

    CAS  PubMed  Google Scholar 

  64. Desruisseaux MS, Gulinello M, Smith DN, Lee SC, Tsuji M, Weiss LM, et al. Cognitive dysfunction in mice infected with Plasmodium berghei strain ANKA. J Infect Dis. 2008;197(11):1621–7. PubMed PMID: 18419550, Pubmed Central PMCID: 2692506.

    PubMed Central  PubMed  Google Scholar 

  65. Migasena P, Maegraith BG. The movement of the dye (disulphine blue) from blood into brain tissue examined by dye method in normal and Plasmodium berghei infected mice. Med J Malaya. 1968;22(3):252. PubMed PMID: 4234391.

    CAS  PubMed  Google Scholar 

  66. Ma N, Madigan MC, Chan-Ling T, Hunt NH. Compromised blood-nerve barrier, astrogliosis, and myelin disruption in optic nerves during fatal murine cerebral malaria. Glia. 1997;19(2):135–51. PubMed PMID: 9034830.

    CAS  PubMed  Google Scholar 

  67. Thumwood CM, Hunt NH, Clark IA, Cowden WB. Breakdown of the blood-brain barrier in murine cerebral malaria. Parasitology. 1988;96(Pt 3):579–89. PubMed PMID: 2457201.

    PubMed  Google Scholar 

  68. van der Heyde HC, Bauer P, Sun G, Chang WL, Yin L, Fuseler J, et al. Assessing vascular permeability during experimental cerebral malaria by a radiolabeled monoclonal antibody technique. Infect Immun. 2001;69(5):3460–5. PubMed PMID: 11292776, Pubmed Central PMCID: 98312.

    PubMed Central  PubMed  Google Scholar 

  69. Ampawong S, Combes V, Hunt NH, Radford J, Chan-Ling T, Pongponratn E, et al. Quantitation of brain edema and localisation of aquaporin 4 expression in relation to susceptibility to experimental cerebral malaria. Int J Clin Exp Pathol. 2011;4(6):566–74. PubMed PMID: 21904632, Pubmed Central PMCID: 3160608.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Penet MF, Viola A, Confort-Gouny S, Le Fur Y, Duhamel G, Kober F, et al. Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema. J Neurosci. 2005;25(32):7352–8. PubMed PMID: 16093385.

    CAS  PubMed  Google Scholar 

  71. Szklarczyk A, Stins M, Milward EA, Ryu H, Fitzsimmons C, Sullivan D, et al. Glial activation and matrix metalloproteinase release in cerebral malaria. J Neurovirol. 2007;13(1):2–10. PubMed PMID: 17454443.

    CAS  PubMed  Google Scholar 

  72. Lakhan SE, Kirchgessner A, Tepper D, Leonard A. Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol. 2013;4:32. PubMed PMID: 23565108, Pubmed Central PMCID: 3615191.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Rest JR. Cerebral malaria in inbred mice. I. A new model and its pathology. Trans R Soc Trop Med Hyg. 1982;76(3):410–5. PubMed PMID: 7051459.

    CAS  PubMed  Google Scholar 

  74. Riley EM, Couper KN, Helmby H, Hafalla JC, de Souza JB, Langhorne J, et al. Neuropathogenesis of human and murine malaria. Trends Parasitol. 2010;26(6):277–8. PubMed PMID: 20338809.

    PubMed  Google Scholar 

  75. Baptista FG, Pamplona A, Pena AC, Mota MM, Pied S, Vigario AM. Accumulation of Plasmodium berghei-infected red blood cells in the brain is crucial for the development of cerebral malaria in mice. Infect Immun. 2010;78(9):4033–9. PubMed PMID: 20605973, Pubmed Central PMCID: 2937458.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Franke-Fayard B, Janse CJ, Cunha-Rodrigues M, Ramesar J, Buscher P, Que I, et al. Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration. Proc Natl Acad Sci U S A. 2005;102(32):11468–73. PubMed PMID: 16051702, Pubmed Central PMCID: 1183563.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Amante FH, Haque A, Stanley AC, Rivera Fde L, Randall LM, Wilson YA, et al. Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria. J Immunol. 2010;185(6):3632–42. PubMed PMID: 20720206.

    CAS  PubMed  Google Scholar 

  78. Grau GE, Piguet PF, Engers HD, Louis JA, Vassalli P, Lambert PH. L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria. J Immunol. 1986;137(7):2348–54. PubMed PMID: 3093572.

    CAS  PubMed  Google Scholar 

  79. Cox-Singh J, Hiu J, Lucas SB, Divis PC, Zulkarnaen M, Chandran P, et al. Severe malaria - a case of fatal Plasmodium knowlesi infection with post-mortem findings: a case report. Malar J. 2010;9:10. PubMed PMID: 20064229, Pubmed Central PMCID: 2818646.

    PubMed Central  PubMed  Google Scholar 

  80. Cox-Singh J, Singh B, Daneshvar C, Planche T, Parker-Williams J, Krishna S. Anti-inflammatory cytokines predominate in acute human Plasmodium knowlesi infections. PLoS One. 2011;6(6):e20541. PubMed PMID: 21687657, Pubmed Central PMCID: 3110641.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Fujioka H, Millet P, Maeno Y, Nakazawa S, Ito Y, Howard RJ, et al. A nonhuman primate model for human cerebral malaria: rhesus monkeys experimentally infected with Plasmodium fragile. Exp Parasitol. 1994;78(4):371–6. PubMed PMID: 7515825.

    CAS  PubMed  Google Scholar 

  82. Nakano Y, Fujioka H, Luc KD, Rabbege JR, Todd GD, Collins WE, et al. A correlation of the sequestration rate of Plasmodium coatneyi-infected erythrocytes in cerebral and subcutaneous tissues of a rhesus monkey. Am J Trop Med Hyg. 1996;55(3):311–4. PubMed PMID: 8842121.

    CAS  PubMed  Google Scholar 

  83. Smith CD, Brown AE, Nakazawa S, Fujioka H, Aikawa M. Multi-organ erythrocyte sequestration and ligand expression in rhesus monkeys infected with Plasmodium coatneyi malaria. Am J Trop Med Hyg. 1996;55(4):379–83. PubMed PMID: 8916792.

    CAS  PubMed  Google Scholar 

  84. Kawai S, Sugiyama M. Imaging analysis of the brain in a primate model of cerebral malaria. Acta Trop. 2010;114(3):152–6. PubMed PMID: 19467218.

    PubMed  Google Scholar 

  85. Moreno A, Cabrera-Mora M, Garcia A, Orkin J, Strobert E, Barnwell JW, et al. Plasmodium coatneyi in rhesus macaques replicates the multi-systemic dysfunction of severe malaria in humans. Infect Immun. 2013;81(6):1889–904. PubMed PMID: 23509137.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Tongren JE, Yang C, Collins WE, Sullivan JS, Lal AA, Xiao L. Expression of proinflammatory cytokines in four regions of the brain in Macaque mulatta (rhesus) monkeys infected with Plasmodium coatneyi. Am J Trop Med Hyg. 2000;62(4):530–4. PubMed PMID: 11220773.

    CAS  PubMed  Google Scholar 

  87. Gysin J, Aikawa M, Tourneur N, Tegoshi T. Experimental Plasmodium falciparum cerebral malaria in the squirrel monkey Saimiri sciureus. Exp Parasitol. 1992;75(4):390–8. PubMed PMID: 1493871.

    CAS  PubMed  Google Scholar 

  88. Robert C, Peyrol S, Pouvelle B, Gay-Andrieu F, Gysin J. Ultrastructural aspects of Plasmodium falciparum-infected erythrocyte adherence to endothelial cells of Saimiri brain microvasculature. Am J Trop Med Hyg. 1996;54(2):169–77. PubMed PMID: 8619443.

    CAS  PubMed  Google Scholar 

  89. Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, et al. Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991;352(6336):595–600. PubMed PMID: 1865923.

    CAS  PubMed  Google Scholar 

  90. Bull PC, Lowe BS, Kortok M, Molyneux CS, Newbold CI, Marsh K. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat Med. 1998;4(3):358–60. PubMed PMID: 9500614.

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Gupta S, Snow RW, Donnelly CA, Marsh K, Newbold C. Immunity to non-cerebral severe malaria is acquired after one or two infections. Nat Med. 1999;5(3):340–3. PubMed PMID: 10086393.

    CAS  PubMed  Google Scholar 

  92. Snow RW, Nahlen B, Palmer A, Donnelly CA, Gupta S, Marsh K. Risk of severe malaria among African infants: direct evidence of clinical protection during early infancy. J Infect Dis. 1998;177(3):819–22. PubMed PMID: 9498474.

    CAS  PubMed  Google Scholar 

  93. Riley EM. Is T-cell priming required for initiation of pathology in malaria infections? Immunol Today. 1999;20(5):228–33. PubMed PMID: 10322302.

    CAS  PubMed  Google Scholar 

  94. Grau GE, Piguet PF, Vassalli P, Lambert PH. Tumor-necrosis factor and other cytokines in cerebral malaria: experimental and clinical data. Immunol Rev. 1989;112:49–70. PubMed PMID: 2575074.

    CAS  PubMed  Google Scholar 

  95. Kwiatkowski D, Hill AV, Sambou I, Twumasi P, Castracane J, Manogue KR, et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet. 1990;336(8725):1201–4. PubMed PMID: 1978068.

    CAS  PubMed  Google Scholar 

  96. Dodoo D, Omer FM, Todd J, Akanmori BD, Koram KA, Riley EM. Absolute levels and ratios of proinflammatory and anti-inflammatory cytokine production in vitro predict clinical immunity to Plasmodium falciparum malaria. J Infect Dis. 2002;185(7):971–9. PubMed PMID: 11920322.

    CAS  PubMed  Google Scholar 

  97. Elhassan IM, Hviid L, Satti G, Akerstrom B, Jakobsen PH, Jensen JB, et al. Evidence of endothelial inflammation, T cell activation, and T cell reallocation in uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg. 1994;51(3):372–9. PubMed PMID: 7524374.

    CAS  PubMed  Google Scholar 

  98. Loizon S, Boeuf P, Tetteh JK, Goka B, Obeng-Adjei G, Kurtzhals JA, et al. V beta profiles in African children with acute cerebral or uncomplicated malaria: very focused changes among a remarkable global stability. Microbes Infect. 2007;9(11):1252–9. PubMed PMID: 17890120.

    CAS  PubMed  Google Scholar 

  99. Artavanis-Tsakonas K, Riley EM. Innate immune response to malaria: rapid induction of IFN-gamma from human NK cells by live Plasmodium falciparum-infected erythrocytes. J Immunol. 2002;169(6):2956–63. PubMed PMID: 12218109.

    CAS  PubMed  Google Scholar 

  100. Waterfall M, Black A, Riley E. Gammadelta+ T cells preferentially respond to live rather than killed malaria parasites. Infect Immun. 1998;66(5):2393–8. PubMed PMID: 9573139, Pubmed Central PMCID: 108213.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Walther M, Jeffries D, Finney OC, Njie M, Ebonyi A, Deininger S, et al. Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog. 2009;5(4):e1000364. PubMed PMID: 19343213, Pubmed Central PMCID: 2658808.

    PubMed Central  PubMed  Google Scholar 

  102. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994; 371(6497):508–10. PubMed PMID: 7935762.

    CAS  PubMed  Google Scholar 

  103. Riley EM, Wahl S, Perkins DJ, Schofield L. Regulating immunity to malaria. Parasite Immunol. 2006;28(1–2):35–49. PubMed PMID: 16438675.

    CAS  PubMed  Google Scholar 

  104. Sherry BA, Alava G, Tracey KJ, Martiney J, Cerami A, Slater AF. Malaria-specific metabolite hemozoin mediates the release of several potent endogenous pyrogens (TNF, MIP-1 alpha, and MIP-1 beta) in vitro, and altered thermoregulation in vivo. J Inflamm. 1995;45(2):85–96. PubMed PMID: 7583361.

    CAS  PubMed  Google Scholar 

  105. Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med. 2005;201(1):19–25. PubMed PMID: 15630134, Pubmed Central PMCID: 2212757.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Deshpande P, Shastry P. Modulation of cytokine profiles by malaria pigment – hemozoin: role of IL-10 in suppression of proliferative responses of mitogen stimulated human PBMC. Cytokine. 2004;28(6):205–13. PubMed PMID: 15566949.

    CAS  PubMed  Google Scholar 

  107. Schwarzer E, Turrini F, Ulliers D, Giribaldi G, Ginsburg H, Arese P. Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J Exp Med. 1992;176(4):1033–41. PubMed PMID: 1402649, Pubmed Central PMCID: 2119406.

    CAS  PubMed  Google Scholar 

  108. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653–62. PubMed PMID: 15811985.

    CAS  PubMed  Google Scholar 

  109. Lee SK, Ding JL. A perspective on the role of extracellular hemoglobin on the innate immune system. DNA Cell Biol. 2013;32(2):36–40. PubMed PMID: 23249270, Pubmed Central PMCID: 3557431.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. John CC, Opika-Opoka R, Byarugaba J, Idro R, Boivin MJ. Low levels of RANTES are associated with mortality in children with cerebral malaria. J Infect Dis. 2006;194(6):837–45. PubMed PMID: 16941352.

    PubMed  Google Scholar 

  111. Moxon CA, Heyderman RS, Wassmer SC. Dysregulation of coagulation in cerebral malaria. Mol Biochem Parasitol. 2009;166(2):99–108. PubMed PMID: 19450727.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Tripathi AK, Sha W, Shulaev V, Stins MF, Sullivan Jr DJ. Plasmodium falciparum-infected erythrocytes induce NF-kappaB regulated inflammatory pathways in human cerebral endothelium. Blood. 2009;114(19):4243–52. PubMed PMID: 19713460, Pubmed Central PMCID: 2925626.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. de Mendonca VR, Goncalves MS, Barral-Netto M. The host genetic diversity in malaria infection. J Trop Med. 2012;2012:940616. PubMed PMID: 23316245, Pubmed Central PMCID: 3532872.

    PubMed Central  PubMed  Google Scholar 

  114. Cappadoro M, Giribaldi G, O’Brien E, Turrini F, Mannu F, Ulliers D, et al. Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood. 1998;92(7):2527–34. PubMed PMID: 9746794.

    CAS  PubMed  Google Scholar 

  115. Sambo MR, Trovoada MJ, Benchimol C, Quinhentos V, Goncalves L, Velosa R, et al. Transforming growth factor beta 2 and heme oxygenase 1 genes are risk factors for the cerebral malaria syndrome in Angolan children. PLoS One. 2010;5(6):e11141. PubMed PMID: 20585394, Pubmed Central PMCID: 2886838.

    PubMed Central  PubMed  Google Scholar 

  116. Takeda M, Kikuchi M, Ubalee R, Na-Bangchang K, Ruangweerayut R, Shibahara S, et al. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to cerebral malaria in Myanmar. Jpn J Infect Dis. 2005;58(5):268–71. PubMed PMID: 16249618.

    CAS  PubMed  Google Scholar 

  117. Mendonca VR, Luz NF, Santos NJ, Borges VM, Goncalves MS, Andrade BB, et al. Association between the haptoglobin and heme oxygenase 1 genetic profiles and soluble CD163 in susceptibility to and severity of human malaria. Infect Immun. 2012;80(4):1445–54. PubMed PMID: 22290142, Pubmed Central PMCID: 3318432.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Sam-Agudu NA, Greene JA, Opoka RO, Kazura JW, Boivin MJ, Zimmerman PA, et al. TLR9 polymorphisms are associated with altered IFN-gamma levels in children with cerebral malaria. Am J Trop Med Hyg. 2010;82(4):548–55. PubMed PMID: 20348497, Pubmed Central PMCID: 2844552.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, et al. Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci U S A. 2006;103(1):177–82. PubMed PMID: 16371473, Pubmed Central PMCID: 1324982.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Warrell DA, Looareesuwan S, Phillips RE, White NJ, Warrell MJ, Chapel HM, et al. Function of the blood-cerebrospinal fluid barrier in human cerebral malaria: rejection of the permeability hypothesis. Am J Trop Med Hyg. 1986;35(5):882–9. PubMed PMID: 2429567.

    CAS  PubMed  Google Scholar 

  121. Brown H, Hien TT, Day N, Mai NT, Chuong LV, Chau TT, et al. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol. 1999;25(4):331–40. PubMed PMID: 10476050.

    CAS  PubMed  Google Scholar 

  122. Brown H, Rogerson S, Taylor T, Tembo M, Mwenechanya J, Molyneux M, et al. Blood-brain barrier function in cerebral malaria in Malawian children. Am J Trop Med Hyg. 2001;64(3–4):207–13. PubMed PMID: 11442219.

    CAS  PubMed  Google Scholar 

  123. Dorovini-Zis K, Schmidt K, Huynh H, Fu W, Whitten RO, Milner D, et al. The neuropathology of fatal cerebral malaria in Malawian children. Am J Pathol. 2011;178(5):2146–58. PubMed PMID: 21514429, Pubmed Central PMCID: 3081150.

    PubMed Central  PubMed  Google Scholar 

  124. Renia L, Wu Howland S, Claser C, Charlotte Gruner A, Suwanarusk R, Hui Teo T, et al. Cerebral malaria: mysteries at the blood-brain barrier. Virulence. 2012;3(2):193–201. PubMed PMID: 22460644, Pubmed Central PMCID: 3396698.

    PubMed Central  PubMed  Google Scholar 

  125. Clark IA, Cowden WB. Roles of TNF in malaria and other parasitic infections. Immunol Ser. 1992;56:365–407. PubMed PMID: 1550869.

    CAS  PubMed  Google Scholar 

  126. Wong D, Dorovini-Zis K, Vincent SR. Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. Exp Neurol. 2004;190(2):446–55. PubMed PMID: 15530883.

    CAS  PubMed  Google Scholar 

  127. Yuan SY. Signal transduction pathways in enhanced microvascular permeability. Microcirculation. 2000;7(6 Pt 1):395–403. PubMed PMID: 11142336.

    CAS  PubMed  Google Scholar 

  128. Wassmer SC, Combes V, Candal FJ, Juhan-Vague I, Grau GE. Platelets potentiate brain endothelial alterations induced by Plasmodium falciparum. Infect Immun. 2006;74(1):645–53. PubMed PMID: 16369021, Pubmed Central PMCID: 1346683.

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Esamai F, Ernerudh J, Janols H, Welin S, Ekerfelt C, Mining S, et al. Cerebral malaria in children: serum and cerebrospinal fluid TNF-alpha and TGF-beta levels and their relationship to clinical outcome. J Trop Pediatr. 2003;49(4):216–23. PubMed PMID: 12929882.

    PubMed  Google Scholar 

  130. Wassmer SC, de Souza JB, Frere C, Candal FJ, Juhan-Vague I, Grau GE. 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(2): 1180–4. PubMed PMID: 16394007.

    CAS  PubMed  Google Scholar 

  131. Jambou R, Combes V, Jambou MJ, Weksler BB, Couraud PO, Grau GE. Plasmodium falciparum adhesion on human brain microvascular endothelial cells involves transmigration-like cup formation and induces opening of intercellular junctions. PLoS Pathog. 2010;6(7): e1001021. PubMed PMID: 20686652.

    PubMed Central  PubMed  Google Scholar 

  132. Pino P, Taoufiq Z, Nitcheu J, Vouldoukis I, Mazier D. Blood-brain barrier breakdown during cerebral malaria: suicide or murder? Thromb Haemost. 2005;94(2):336–40. PubMed PMID: 16113823.

    CAS  PubMed  Google Scholar 

  133. Pino P, Vouldoukis I, Kolb JP, Mahmoudi N, Desportes-Livage I, Bricaire F, et al. Plasmodium falciparum – infected erythrocyte adhesion induces caspase activation and apoptosis in human endothelial cells. J Infect Dis. 2003;187(8):1283–90. PubMed PMID: 12696008.

    CAS  PubMed  Google Scholar 

  134. Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, et al. Pericytes regulate the blood-brain barrier. Nature. 2010;468(7323):557–61. PubMed PMID: 20944627.

    CAS  PubMed  Google Scholar 

  135. Sa-Pereira I, Brites D, Brito MA. Neurovascular unit: a focus on pericytes. Mol Neurobiol. 2012;45(2):327–47. PubMed PMID: 22371274.

    CAS  PubMed  Google Scholar 

  136. Dalkara T, Gursoy-Ozdemir Y, Yemisci M. Brain microvascular pericytes in health and disease. Acta Neuropathol. 2011;122(1):1–9. PubMed PMID: 21656168.

    PubMed  Google Scholar 

  137. Kovac A, Erickson MA, Banks WA. Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide. J Neuroinflammation. 2011;8:139. PubMed PMID: 21995440, Pubmed Central PMCID: 3207972.

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Medana IM, Idro R, Newton CR. Axonal and astrocyte injury markers in the cerebrospinal fluid of Kenyan children with severe malaria. J Neurol Sci. 2007;258(1–2):93–8. PubMed PMID: 17459417.

    PubMed  Google Scholar 

  139. Stirling DP, Stys PK. Mechanisms of axonal injury: internodal nanocomplexes and calcium deregulation. Trends Mol Med. 2010;16(4):160–70. PubMed PMID: 20207196, Pubmed Central PMCID: 2976657.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Dolinak D, Smith C, Graham DI. Hypoglycaemia is a cause of axonal injury. Neuropathol Appl Neurobiol. 2000;26(5):448–53. PubMed PMID: 11054185.

    CAS  PubMed  Google Scholar 

  141. Kaur B, Rutty GN, Timperley WR. The possible role of hypoxia in the formation of axonal bulbs. J Clin Pathol. 1999;52(3):203–9. PubMed PMID: 10450180, Pubmed Central PMCID: 501080.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Schluesener HJ, Kremsner PG, Meyermann R. Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells. Acta Neuropathol. 1998;96(6):575–80. PubMed PMID: 9845287.

    CAS  PubMed  Google Scholar 

  143. Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, et al. Control of synaptic strength by glial TNFalpha. Science. 2002;295(5563):2282–5. PubMed PMID: 11910117.

    CAS  PubMed  Google Scholar 

  144. Pickering M, Cumiskey D, O’Connor JJ. Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol. 2005;90(5):663–70. PubMed PMID: 15944202.

    CAS  PubMed  Google Scholar 

  145. Li N, Worthmann H, Deb M, Chen S, Weissenborn K. Nitric oxide (NO) and asymmetric dimethylarginine (ADMA): their pathophysiological role and involvement in intracerebral hemorrhage. Neurol Res. 2011;33(5):541–8. PubMed PMID: 21669125.

    CAS  PubMed  Google Scholar 

  146. Weiss G, Thuma PE, Biemba G, Mabeza G, Werner ER, Gordeuk VR. Cerebrospinal fluid levels of biopterin, nitric oxide metabolites, and immune activation markers and the clinical course of human cerebral malaria. J Infect Dis. 1998;177(4):1064–8. PubMed PMID: 9534983.

    CAS  PubMed  Google Scholar 

  147. Agbenyega T, Angus B, Bedu-Addo G, Baffoe-Bonnie B, Griffin G, Vallance P, et al. Plasma nitrogen oxides and blood lactate concentrations in Ghanaian children with malaria. Trans R Soc Trop Med Hyg. 1997;91(3):298–302. PubMed PMID: 9231201.

    CAS  PubMed  Google Scholar 

  148. Clark IA, Awburn MM, Whitten RO, Harper CG, Liomba NG, Molyneux ME, et al. Tissue distribution of migration inhibitory factor and inducible nitric oxide synthase in falciparum malaria and sepsis in African children. Malar J. 2003;2:6. PubMed PMID: 12716455, Pubmed Central PMCID: 154094.

    PubMed Central  PubMed  Google Scholar 

  149. Wolf A, Zalpour C, Theilmeier G, Wang BY, Ma A, Anderson B, et al. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol. 1997;29(3):479–85. PubMed PMID: 9060881.

    CAS  PubMed  Google Scholar 

  150. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991;88(11):4651–5. PubMed PMID: 1675786, Pubmed Central PMCID: 51723.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Garthwaite J. Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci. 2008;27(11):2783–802. PubMed PMID: 18588525, Pubmed Central PMCID: 2610389.

    PubMed Central  PubMed  Google Scholar 

  152. Guix FX, Uribesalgo I, Coma M, Munoz FJ. The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol. 2005;76(2):126–52. PubMed PMID: 16115721.

    CAS  PubMed  Google Scholar 

  153. Contestabile A. Role of nitric oxide in cerebellar development and function: focus on granule neurons. Cerebellum. 2012;11(1):50–61. PubMed PMID: 21104176.

    CAS  PubMed  Google Scholar 

  154. Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, et al. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med. 2007;204(11):2693–704. PubMed PMID: 17954570, Pubmed Central PMCID: 2118490.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, 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(4):602–8. PubMed PMID: 18605903, Pubmed Central PMCID: 2709993.

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Piera K, 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(44):17097–102. PubMed PMID: 18957536.

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Hawkes M, Opoka RO, Namasopo S, Miller C, Thorpe KE, Lavery JV, et al. Inhaled nitric oxide for the adjunctive therapy of severe malaria: protocol for a randomized controlled trial. Trials. 2011;12:176. PubMed PMID: 21752262, Pubmed Central PMCID: 3151218.

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Higgins SJ, Kain KC, Liles WC. Immunopathogenesis of falciparum malaria: implications for adjunctive therapy in the management of severe and cerebral malaria. Expert Rev Anti Infect Ther. 2011;9(9):803–19. PubMed PMID: 21905788.

    PubMed  Google Scholar 

  159. Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP, Frangos JA, et al. Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med. 2006;12(12):1417–22. PubMed PMID: 17099710.

    CAS  PubMed  Google Scholar 

  160. Ferroni P, Vazzana N, Riondino S, Cuccurullo C, Guadagni F, Davi G. Platelet function in health and disease: from molecular mechanisms, redox considerations to novel therapeutic opportunities. Antioxid Redox Signal. 2012;17(10):1447–85. PubMed PMID: 22458931.

    CAS  PubMed  Google Scholar 

  161. Bernassola F, Rossi A, Melino G. Regulation of transglutaminases by nitric oxide. Ann N Y Acad Sci. 1999;887:83–91. PubMed PMID: 10668466.

    CAS  PubMed  Google Scholar 

  162. Zhou Z, Yee DL, Guchhait P. Molecular link between intravascular hemolysis and vascular occlusion in sickle cell disease. Curr Vasc Pharmacol. 2012;10(6):756–61. PubMed PMID: 22272904.

    CAS  PubMed  Google Scholar 

  163. Buhrer C, Felderhoff-Mueser U, Wellmann S. Erythropoietin and ischemic conditioning – why two good things may be bad. Acta Paediatr. 2007;96(6):787–9. PubMed PMID: 17537001.

    PubMed  Google Scholar 

  164. Kaiser K, Texier A, Ferrandiz J, Buguet A, Meiller A, Latour C, et al. Recombinant human erythropoietin prevents the death of mice during cerebral malaria. J Infect Dis. 2006;193(7):987–95. PubMed PMID: 16518761.

    CAS  PubMed  Google Scholar 

  165. Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals JA. Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar J. 2008;7:3. PubMed PMID: 18179698.

    PubMed Central  PubMed  Google Scholar 

  166. Casals-Pascual C, Idro R, Gicheru N, Gwer S, Kitsao B, Gitau E, et al. High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria. Proc Natl Acad Sci U S A. 2008;105(7):2634–9. PubMed PMID: 18263734.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Medana IM, Day NP, Hien TT, White NJ, Turner GD. Erythropoietin and its receptors in the brainstem of adults with fatal falciparum malaria. Malar J. 2009;8:261. PubMed PMID: 19930602, Pubmed Central PMCID: 2785829.

    PubMed Central  PubMed  Google Scholar 

  168. Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40(12):e647–56. PubMed PMID: 19834012.

    CAS  PubMed  Google Scholar 

  169. Picot S, Bienvenu AL, Konate S, Sissoko S, Barry A, Diarra E, et al. Safety of epoietin beta-quinine drug combination in children with cerebral malaria in Mali. Malar J. 2009;8:169. PubMed PMID: 19630971, Pubmed Central PMCID: 2723129.

    PubMed Central  PubMed  Google Scholar 

  170. Najjar SS, Rao SV, Melloni C, Raman SV, Povsic TJ, Melton L, et al. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA. 2011;305(18):1863–72. PubMed PMID: 21558517, Pubmed Central PMCID: 3486644.

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Lapchak PA. Erythropoietin molecules to treat acute ischemic stroke: a translational dilemma! Expert Opin Investig Drugs. 2010;19(10):1179–86. PubMed PMID: 20828227, Pubmed Central PMCID: 2947745.

    CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Global Pediatrics, University of Minnesota Medical School, 2001 6TH ST SE, 3-206 MTRF, Minneapolis, MN, 55455, USA

    Gregory S. Park

  2. Division of Global Pediatrics, University of Minnesota Medical School, 717 Delaware St SE, Rm 366, Minneapolis, MN, 55414, USA

    Chandy C. John M.D., M.P.H.

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  1. Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA

    Phillip K. Peterson

  2. Department of Biochemistry Department of Molecular Biology, University of Miami School of Medicine, Miami, Florida, USA

    Michal Toborek

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Park, G.S., John, C.C. (2014). Cerebral Malaria. In: Peterson, P., Toborek, M. (eds) Neuroinflammation and Neurodegeneration. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1071-7_19

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