1932

Abstract

Malaria remains a major public health threat in tropical and subtropical regions across the world. Even though less than 1% of malaria infections are fatal, this leads to about 430,000 deaths per year, predominantly in young children in sub-Saharan Africa. Therefore, it is imperative to understand why a subset of infected individuals develop severe syndromes and some of them die and what differentiates these cases from the majority that recovers. Here, we discuss progress made during the past decade in our understanding of malaria pathogenesis, focusing on the major human parasite .

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2020-01-24
2024-12-06
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Literature Cited

  1. 1. 
    Kwiatkowski DP. 2005. How malaria has affected the human genome and what human genetics can teach us about malaria. Am. J. Hum. Genet. 77:171–92
    [Google Scholar]
  2. 2. 
    Rodrigues PT, Valdivia HO, de Oliveira TC, Alves JMP, Duarte A et al. 2018. Human migration and the spread of malaria parasites to the New World. Sci. Rep. 8:1993
    [Google Scholar]
  3. 3. 
    Garnham PC. 1988. History of discoveries of malaria parasites and of their life cycles. Hist. Philos. Life Sci. 10:93–108
    [Google Scholar]
  4. 4. 
    WHO (World Health Organ.) 2018. World Malaria Report 2018 Geneva: WHO
    [Google Scholar]
  5. 5. 
    RTS,S Clin. Trials Partnersh 2015. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386:31–45
    [Google Scholar]
  6. 6. 
    Olotu A, Fegan G, Wambua J, Nyangweso G, Leach A et al. 2016. Seven-year efficacy of RTS,S/AS01 malaria vaccine among young African children. N. Engl. J. Med. 374:2519–29
    [Google Scholar]
  7. 7. 
    Singh B, Daneshvar C. 2013. Human infections and detection of Plasmodium knowlesi. Clin. Microbiol. Rev 26:165–84
    [Google Scholar]
  8. 8. 
    Imwong M, Madmanee W, Suwannasin K, Kunasol C, Peto TJ, Tripura R et al. 2018. Asymptomatic natural human infections with the simian malaria parasites Plasmodium cynomolgi and Plasmodium knowlesi. J. Infect. Dis 219:695–702
    [Google Scholar]
  9. 9. 
    Lalremruata A, Magris M, Vivas-Martinez S, Koehler M, Esen M et al. 2015. Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon. EBioMedicine 2:1186–92
    [Google Scholar]
  10. 10. 
    Haldar K, Murphy SC, Milner DA, Taylor TE 2007. Malaria: mechanisms of erythrocytic infection and pathological correlates of severe disease. Annu. Rev. Pathol. Mech. Dis. 2:217–49
    [Google Scholar]
  11. 11. 
    Marsh K, Forster D, Waruiru C, Mwangi I, Winstanley M et al. 1995. Indicators of life-threatening malaria in African children. N. Engl. J. Med. 332:1399–404
    [Google Scholar]
  12. 12. 
    Taylor WRJ, Hanson J, Turner GDH, White NJ, Dondorp AM 2012. Respiratory manifestations of malaria. Chest 142:492–505
    [Google Scholar]
  13. 13. 
    Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS et al. 2004. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat. Med. 10:143–45
    [Google Scholar]
  14. 14. 
    MacCormick IJ, Beare NA, Taylor TE, Barrera V, White VA et al. 2014. Cerebral malaria in children: using the retina to study the brain. Brain 137:2119–42
    [Google Scholar]
  15. 15. 
    Maude RJ, Beare NA, Abu Sayeed A, Chang CC, Charunwatthana P et al. 2009. The spectrum of retinopathy in adults with Plasmodium falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 103:665–71
    [Google Scholar]
  16. 16. 
    Postels DG, Taylor TE, Molyneux M, Mannor K, Kaplan PW et al. 2012. Neurologic outcomes in retinopathy-negative cerebral malaria survivors. Neurology 79:1268–72
    [Google Scholar]
  17. 17. 
    Mallewa M, Vallely P, Faragher B, Banda D, Klapper P et al. 2013. Viral CNS infections in children from a malaria-endemic area of Malawi: a prospective cohort study. Lancet. Glob. Health 1:e153–60
    [Google Scholar]
  18. 18. 
    Seydel KB, Kampondeni SD, Valim C, Potchen MJ, Milner DA et al. 2015. Brain swelling and death in children with cerebral malaria. N. Engl. J. Med. 372:1126–37
    [Google Scholar]
  19. 19. 
    Potchen MJ, Kampondeni SD, Seydel KB, Haacke EM, Sinyangwe SS et al. 2018. 1.5 Tesla magnetic resonance imaging to investigate potential etiologies of brain swelling in pediatric cerebral malaria. Am. J. Trop. Med. Hyg. 98:497–504
    [Google Scholar]
  20. 20. 
    Mohanty S, Benjamin LA, Majhi M, Panda P, Kampondeni S et al. 2017. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the brain. mSphere 2:e00193–17
    [Google Scholar]
  21. 21. 
    Fugate JE, Rabinstein AA. 2015. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 14:914–25
    [Google Scholar]
  22. 22. 
    O'Brien NF, Mutatshi Taty T, Moore-Clingenpeel M, Bodi Mabiala J, Mbaka Pongo J et al. 2018. Transcranial Doppler ultrasonography provides insights into neurovascular changes in children with cerebral malaria. J. Pediatr. 203:116–24.e3
    [Google Scholar]
  23. 23. 
    Barrera V, MacCormick IJC, Czanner G, Hiscott PS, White VA et al. 2018. Neurovascular sequestration in paediatric P. falciparum malaria is visible clinically in the retina. eLife 7:e32208
    [Google Scholar]
  24. 24. 
    Beare NA, Harding SP, Taylor TE, Lewallen S, Molyneux ME 2009. Perfusion abnormalities in children with cerebral malaria and malarial retinopathy. J. Infect. Dis. 199:263–71
    [Google Scholar]
  25. 25. 
    Glover SJ, Maude RJ, Taylor TE, Molyneux ME, Beare NA 2010. Malarial retinopathy and fluorescein angiography findings in a Malawian child with cerebral malaria. Lancet Infect. Dis. 10:440
    [Google Scholar]
  26. 26. 
    Beare NA, Southern C, Chalira C, Taylor TE, Molyneux ME, Harding SP 2004. Prognostic significance and course of retinopathy in children with severe malaria. Arch. Ophthalmol. 122:1141–7
    [Google Scholar]
  27. 27. 
    Zhao Y, MacCormick IJ, Parry DG, Beare NA, Harding SP, Zheng Y 2015. Automated detection of vessel abnormalities on fluorescein angiogram in malarial retinopathy. Sci. Rep. 5:11154
    [Google Scholar]
  28. 28. 
    Marchiafava F, Bignami A. 1892. Sulle febbri malariche estivo-autunnali Rome: Loescher
    [Google Scholar]
  29. 29. 
    Dorovini-Zis K, Schmidt K, Huynh H, Fu W, Whitten RO et al. 2011. The neuropathology of fatal cerebral malaria in Malawian children. Am. J. Pathol. 178:2146–58
    [Google Scholar]
  30. 30. 
    Jaroonvesama N. 1972. Intravascular coagulation in falciparum malaria. Lancet 1:221–23
    [Google Scholar]
  31. 31. 
    Moxon CA, Wassmer SC, Milner DA Jr, Chisala NV, Taylor TE et al. 2013. Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. Blood 122:842–51
    [Google Scholar]
  32. 32. 
    Turner L, Lavstsen T, Berger SS, Wang CW, Petersen JE et al. 2013. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498:502–5
    [Google Scholar]
  33. 33. 
    Kessler A, Dankwa S, Bernabeu M, Harawa V, Danziger SA et al. 2017. Linking EPCR-binding PfEMP1 to brain swelling in pediatric cerebral malaria. Cell Host Microbe 22:601–14.e5
    [Google Scholar]
  34. 34. 
    Milner DA Jr, Whitten RO, Kamiza S, Carr R, Liomba G et al. 2014. The systemic pathology of cerebral malaria in African children. Front. Cell. Infect. Microbiol. 4:104
    [Google Scholar]
  35. 35. 
    Greiner J, Dorovini-Zis K, Taylor TE, Molyneux ME, Beare NA et al. 2015. Correlation of hemorrhage, axonal damage, and blood–tissue barrier disruption in brain and retina of Malawian children with fatal cerebral malaria. Front. Cell. Infect. Microbiol. 5:18
    [Google Scholar]
  36. 36. 
    Plewes K, Turner GDH, Dondorp AM 2018. Pathophysiology, clinical presentation, and treatment of coma and acute kidney injury complicating falciparum malaria. Curr. Opin. Infect. Dis. 31:69–77
    [Google Scholar]
  37. 37. 
    Plewes K, Kingston HWF, Ghose A, Maude RJ, Herdman MT et al. 2017. Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study. BMC Infect. Dis. 17:313
    [Google Scholar]
  38. 38. 
    Trang TT, Phu NH, Vinh H, Hien TT, Cuong BM et al. 1992. Acute renal failure in patients with severe falciparum malaria. Clin. Infect. Dis. 15:874–80
    [Google Scholar]
  39. 39. 
    Plewes K, Kingston HWF, Ghose A, Wattanakul T, Hassan MMU et al. 2018. Acetaminophen as a renoprotective adjunctive treatment in patients with severe and moderately severe falciparum malaria: a randomized, controlled, open-label trial. Clin. Infect. Dis. 67:991–99
    [Google Scholar]
  40. 40. 
    Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI 2005. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434:214–17
    [Google Scholar]
  41. 41. 
    Prasad R, Mishra OP. 2016. Acute kidney injury in children with Plasmodium falciparum malaria: determinants for mortality. Perit. Dial. Int. 36:213–17
    [Google Scholar]
  42. 42. 
    Nguansangiam S, Day NP, Hien TT, Mai NT, Chaisri U et al. 2007. A quantitative ultrastructural study of renal pathology in fatal Plasmodium falciparum malaria. Trop. Med. Int. Health 12:1037–50
    [Google Scholar]
  43. 43. 
    Milner D Jr, Factor R, Whitten R, Carr RA, Kamiza S et al. 2013. Pulmonary pathology in pediatric cerebral malaria. Hum. Pathol. 44:2719–26
    [Google Scholar]
  44. 44. 
    Hanson JP, Lam SW, Mohanty S, Alam S, Pattnaik R et al. 2013. Fluid resuscitation of adults with severe falciparum malaria: effects on acid–base status, renal function, and extravascular lung water. Crit. Care Med. 41:972–81
    [Google Scholar]
  45. 45. 
    Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P et al. 2011. Mortality after fluid bolus in African children with severe infection. N. Engl. J. Med. 364:2483–95
    [Google Scholar]
  46. 46. 
    Levin M, Cunnington AJ, Wilson C, Nadel S, Lang HJ et al. 2019. Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial. Lancet Respir. Med. 7:P581–93
    [Google Scholar]
  47. 47. 
    MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA 1985. Human cerebral malaria: a quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am. J. Pathol. 119:385–401
    [Google Scholar]
  48. 48. 
    Maknitikul S, Luplertlop N, Grau GER, Ampawong S 2017. Dysregulation of pulmonary endothelial protein C receptor and thrombomodulin in severe falciparum malaria–associated ARDS relevant to hemozoin. PLOS ONE 12:e0181674
    [Google Scholar]
  49. 49. 
    English M, Muambi B, Mithwani S, Marsh K 1997. Lactic acidosis and oxygen debt in African children with severe anaemia. QJM 90:563–69
    [Google Scholar]
  50. 50. 
    Buffet PA, Safeukui I, Deplaine G, Brousse V, Prendki V et al. 2011. The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology. Blood 117:381–92
    [Google Scholar]
  51. 51. 
    Herricks T, Antia M, Rathod PK 2009. Deformability limits of Plasmodium falciparum–infected red blood cells. Cell. Microbiol. 11:1340–53
    [Google Scholar]
  52. 52. 
    Angus BJ, Chotivanich K, Udomsangpetch R, White NJ 1997. In vivo removal of malaria parasites from red blood cells without their destruction in acute falciparum malaria. Blood 90:2037–40
    [Google Scholar]
  53. 53. 
    Chotivanich K, Udomsangpetch R, Dondorp A, Williams T, Angus B et al. 2000. The mechanisms of parasite clearance after antimalarial treatment of Plasmodium falciparum malaria. J. Infect. Dis. 182:629–33
    [Google Scholar]
  54. 54. 
    Ndour PA, Larreche S, Mouri O, Argy N, Gay F et al. 2017. Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis. Sci. Transl. Med. 9:eaaf9377
    [Google Scholar]
  55. 55. 
    Joice R, Frantzreb C, Pradham A, Seydel KB, Kamiza S et al. 2016. Evidence for spleen dysfunction in malaria–HIV co-infection in a subset of pediatric patients. Mod. Pathol. 29:381–90
    [Google Scholar]
  56. 56. 
    Ludlow LE, Zhou J, Tippett E, Cheng WJ, Hasang W et al. 2012. HIV-1 inhibits phagocytosis and inflammatory cytokine responses of human monocyte-derived macrophages to P. falciparum infected erythrocytes. PLOS ONE 7:e32102
    [Google Scholar]
  57. 57. 
    White NJ. 2018. Anaemia and malaria. Malar. J. 17:371
    [Google Scholar]
  58. 58. 
    Calis JC, Phiri KS, Faragher EB, Brabin BJ, Bates I et al. 2008. Severe anemia in Malawian children. Malawi Med. J. 28:99–107
    [Google Scholar]
  59. 59. 
    Casanova JL. 2015. Human genetic basis of interindividual variability in the course of infection. PNAS 112:E7118–27
    [Google Scholar]
  60. 60. 
    English M, Waruiru C, Marsh K 1996. Transfusion for respiratory distress in life-threatening childhood malaria. Am. J. Trop. Med. Hyg. 55:525–30
    [Google Scholar]
  61. 61. 
    Lackritz EM, Campbell CC, Ruebush TK 2nd, Hightower AW, Wakube W et al. 1992. Effect of blood transfusion on survival among children in a Kenyan hospital. Lancet 340:524–28
    [Google Scholar]
  62. 62. 
    O'Meara WP, Mwangi TW, Williams TN, McKenzie FE, Snow RW, Marsh K 2008. Relationship between exposure, clinical malaria, and age in an area of changing transmission intensity. Am. J. Trop. Med. Hyg. 79:185–91
    [Google Scholar]
  63. 63. 
    Brand NR, Opoka RO, Hamre KE, John CC 2016. Differing causes of lactic acidosis and deep breathing in cerebral malaria and severe malarial anemia may explain differences in acidosis-related mortality. PLOS ONE 11:e0163728
    [Google Scholar]
  64. 64. 
    Dhabangi A, Ainomugisha B, Cserti-Gazdewich C, Ddungu H, Kyeyune D et al. 2015. Effect of transfusion of red blood cells with longer versus shorter storage duration on elevated blood lactate levels in children with severe anemia: the TOTAL randomized clinical trial. JAMA 314:2514–23
    [Google Scholar]
  65. 65. 
    English M, Ahmed M, Ngando C, Berkley J, Ross A 2002. Blood transfusion for severe anaemia in children in a Kenyan hospital. Lancet 359:494–95
    [Google Scholar]
  66. 66. 
    WHO (World Health Organ.) 2015. Guidelines for the Treatment of Malaria Geneva: WHO. , 3rd ed..
    [Google Scholar]
  67. 67. 
    Pasricha SR, Atkinson SH, Armitage AE, Khandwala S, Veenemans J et al. 2014. Expression of the iron hormone hepcidin distinguishes different types of anemia in African children. Sci. Transl. Med. 6:235re3
    [Google Scholar]
  68. 68. 
    Portugal S, Carret C, Recker M, Armitage AE, Goncalves LA et al. 2011. Host-mediated regulation of superinfection in malaria. Nat. Med. 17:732–37
    [Google Scholar]
  69. 69. 
    Wegmuller R, Bah A, Kendall L, Goheen MM, Mulwa S et al. 2016. Efficacy and safety of hepcidin-based screen-and-treat approaches using two different doses versus a standard universal approach of iron supplementation in young children in rural Gambia: a double-blind randomised controlled trial. BMC Pediatr 16:149
    [Google Scholar]
  70. 70. 
    Church J, Maitland K. 2014. Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review. BMC Med 12:31
    [Google Scholar]
  71. 71. 
    Reddy EA, Shaw AV, Crump JA 2010. Community-acquired bloodstream infections in Africa: a systematic review and meta-analysis. Lancet Infect. Dis. 10:417–32
    [Google Scholar]
  72. 72. 
    Bronzan RN, Taylor TE, Mwenechanya J, Tembo M, Kayira K et al. 2007. Bacteremia in Malawian children with severe malaria: prevalence, etiology, HIV coinfection, and outcome. J. Infect. Dis. 195:895–904
    [Google Scholar]
  73. 73. 
    Scott JA, Berkley JA, Mwangi I, Ochola L, Uyoga S et al. 2011. Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case–control study and a longitudinal study. Lancet 378:1316–23
    [Google Scholar]
  74. 74. 
    Leopold SJ, Ghose A, Allman EL, Kingston HWF, Hossain A et al. 2019. Identifying the components of acidosis in patients with severe P. falciparum malaria using metabolomics. J. Infect. Dis. 219:1766–76
    [Google Scholar]
  75. 75. 
    Cunnington AJ, de Souza JB, Walther M, Riley EM 2011. Malaria impairs resistance to Salmonella through heme- and heme oxygenase–dependent dysfunctional granulocyte mobilization. Nat. Med. 18:120–27
    [Google Scholar]
  76. 76. 
    Nadjm B, Amos B, Mtove G, Ostermann J, Chonya S et al. 2010. WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study. BMJ 340:c1350
    [Google Scholar]
  77. 77. 
    Viebig NK, Wulbrand U, Forster R, Andrews KT, Lanzer M, Knolle PA 2005. Direct activation of human endothelial cells by Plasmodium falciparum–infected erythrocytes. Infect. Immun. 73:3271–77
    [Google Scholar]
  78. 78. 
    Jambou R, Combes V, Jambou MJ, Weksler BB, Couraud PO, Grau GE 2010. Plasmodium falciparum adhesion on human brain microvascular endothelial cells involves transmigration-like cup formation and induces opening of intercellular junctions. PLOS Pathog 6:e1001021
    [Google Scholar]
  79. 79. 
    Griffith JW, Sun T, McIntosh MT, Bucala R 2009. Pure hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid. J. Immunol. 183:5208–20
    [Google Scholar]
  80. 80. 
    Parroche P, Lauw FN, Goutagny N, Latz E, Monks BG et al. 2007. Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. PNAS 104:1919–24
    [Google Scholar]
  81. 81. 
    Kalantari P, DeOliveira RB, Chan J, Corbett Y, Rathinam V et al. 2014. Dual engagement of the NLRP3 and AIM2 inflammasomes by Plasmodium-derived hemozoin and DNA during malaria. Cell Rep 6:196–210
    [Google Scholar]
  82. 82. 
    Lopera-Mesa TM, Mita-Mendoza NK, van de Hoef DL, Doumbia S, Konate D et al. 2012. Plasma uric acid levels correlate with inflammation and disease severity in Malian children with Plasmodium falciparum malaria. PLOS ONE 7:e46424
    [Google Scholar]
  83. 83. 
    Gowda NM, Wu X, Gowda DC 2011. The nucleosome (histone–DNA complex) is the TLR9-specific immunostimulatory component of Plasmodium falciparum that activates DCs. PLOS ONE 6:e20398
    [Google Scholar]
  84. 84. 
    Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF et al. 2007. Characterization of heme as activator of Toll-like receptor 4. J. Biol. Chem. 282:20221–29
    [Google Scholar]
  85. 85. 
    Gillrie MR, Lee K, Gowda DC, Davis SP, Monestier M et al. 2012. Plasmodium falciparum histones induce endothelial proinflammatory response and barrier dysfunction. Am. J. Pathol. 180:1028–39
    [Google Scholar]
  86. 86. 
    Moxon CA, Alhamdi Y, Storm J, Toh J, Ko JY et al. 2019. Parasite histones mediate leak and coagulopathy in cerebral malaria. bioRxiv 563551. https://doi.org/10.1101/563551
    [Crossref]
  87. 87. 
    Fox LL, Taylor TE, Pensulo P, Liomba A, Mpakiza A et al. 2013. Histidine-rich protein 2 plasma levels predict progression to cerebral malaria in Malawian children with Plasmodium falciparum infection. J. Infect. Dis. 208:500–3
    [Google Scholar]
  88. 88. 
    Kariuki SM, Gitau E, Gwer S, Karanja HK, Chengo E et al. 2014. Value of Plasmodium falciparum histidine-rich protein 2 level and malaria retinopathy in distinguishing cerebral malaria from other acute encephalopathies in Kenyan children. J. Infect. Dis. 209:600–9
    [Google Scholar]
  89. 89. 
    Pal P, Daniels BP, Oskman A, Diamond MS, Klein RS, Goldberg DE 2016. Plasmodium falciparum histidine-rich protein II compromises brain endothelial barriers and may promote cerebral malaria pathogenesis. MBio 7:e00617–16
    [Google Scholar]
  90. 90. 
    Pankoui Mfonkeu JB, Gouado I, Fotso Kuate H, Zambou O, Amvam Zollo PH et al. 2010. Elevated cell-specific microparticles are a biological marker for cerebral dysfunctions in human severe malaria. PLOS ONE 5:e13415
    [Google Scholar]
  91. 91. 
    Debs S, Cohen A, Hosseini-Beheshti E, Chimini G, Hunt NH, Grau GER 2019. Interplay of extracellular vesicles and other players in cerebral malaria pathogenesis. Biochim. Biophys. Acta Gen. Subj. 1863:325–31
    [Google Scholar]
  92. 92. 
    Mantel PY, Hoang AN, Goldowitz I, Potashnikova D, Hamza B et al. 2013. Malaria-infected erythrocyte-derived microvesicles mediate cellular communication within the parasite population and with the host immune system. Cell Host Microbe 13:521–34
    [Google Scholar]
  93. 93. 
    Mantel PY, Hjelmqvist D, Walch M, Kharoubi-Hess S, Nilsson S et al. 2016. Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria. Nat. Commun. 7:12727
    [Google Scholar]
  94. 94. 
    Couper KN, Barnes T, Hafalla JC, Combes V, Ryffel B et al. 2010. Parasite-derived plasma microparticles contribute significantly to malaria infection-induced inflammation through potent macrophage stimulation. PLOS Pathog 6:e1000744
    [Google Scholar]
  95. 95. 
    Faille D, Combes V, Mitchell AJ, Fontaine A, Juhan-Vague I et al. 2009. Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium. FASEB J 23:3449–58
    [Google Scholar]
  96. 96. 
    Feintuch CM, Saidi A, Seydel K, Chen G, Goldman-Yassen A et al. 2016. Activated neutrophils are associated with pediatric cerebral malaria vasculopathy in Malawian children. mBio 7:e01300–15
    [Google Scholar]
  97. 97. 
    Lee HJ, Georgiadou A, Walther M, Nwakanma D, Stewart LB et al. 2018. Integrated pathogen load and dual transcriptome analysis of systemic host–pathogen interactions in severe malaria. Sci. Transl. Med. 10:eaar3619
    [Google Scholar]
  98. 98. 
    Nallandhighal S, Park GS, Ho YY, Opoka RO, John CC, Tran TM 2019. Whole-blood transcriptional signatures composed of erythropoietic and NRF2-regulated genes differ between cerebral malaria and severe malarial anemia. J. Infect. Dis. 219:154–64
    [Google Scholar]
  99. 99. 
    Mahanta A, Kar SK, Kakati S, Baruah S 2015. Heightened inflammation in severe malaria is associated with decreased IL-10 expression levels and neutrophils. Innate Immun 21:546–52
    [Google Scholar]
  100. 100. 
    Kho S, Minigo G, Andries B, Leonardo L, Prayoga P et al. 2019. Circulating neutrophil extracellular traps and neutrophil activation are increased in proportion to disease severity in human malaria. J. Infect. Dis. 219:1994–2004
    [Google Scholar]
  101. 101. 
    Abrams ST, Zhang N, Manson J, Liu T, Dart C et al. 2013. Circulating histones are mediators of trauma-associated lung injury. Am. J. Respir. Crit. Care Med. 187:160–69
    [Google Scholar]
  102. 102. 
    Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A et al. 2011. Sickle hemoglobin confers tolerance to Plasmodium infection. Cell 145:398–409
    [Google Scholar]
  103. 103. 
    Reutersward P, Bergstrom S, Orikiiriza J, Lindquist E, Bergstrom S et al. 2018. Levels of human proteins in plasma associated with acute paediatric malaria. Malar. J. 17:426
    [Google Scholar]
  104. 104. 
    Higgins SJ, Purcell LA, Silver KL, Tran V, Crowley V et al. 2016. Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Sci. Transl. Med. 8:358ra128
    [Google Scholar]
  105. 105. 
    Gallego-Delgado J, Basu-Roy U, Ty M, Alique M, Fernandez-Arias C et al. 2016. Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria. J. Clin. Investig. 126:4016–29
    [Google Scholar]
  106. 106. 
    Freeman BD, Martins YC, Akide-Ndunge OB, Bruno FP, Wang H et al. 2016. Endothelin-1 mediates brain microvascular dysfunction leading to long-term cognitive impairment in a model of experimental cerebral malaria. PLOS Pathog 12:e1005477
    [Google Scholar]
  107. 107. 
    Martins YC, Freeman BD, Akide Ndunge OB, Weiss LM, Tanowitz HB, Desruisseaux MS 2016. Endothelin-1 treatment induces an experimental cerebral malaria-like syndrome in C57BL/6 mice infected with Plasmodium berghei NK65. Am. J. Pathol. 186:2957–69
    [Google Scholar]
  108. 108. 
    Andrade BB, Reis-Filho A, Souza-Neto SM, Clarencio J, Camargo LM et al. 2010. Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance. Malar. J. 9:13
    [Google Scholar]
  109. 109. 
    Freitas do Rosario AP, Lamb T, Spence P, Stephens R, Lang A et al. 2012. IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J. Immunol. 188:1178–90
    [Google Scholar]
  110. 110. 
    Portugal S, Moebius J, Skinner J, Doumbo S, Doumtabe D et al. 2014. Exposure-dependent control of malaria-induced inflammation in children. PLOS Pathog 10:e1004079
    [Google Scholar]
  111. 111. 
    Boyle MJ, Jagannathan P, Bowen K, McIntyre TI, Vance HM et al. 2017. The development of Plasmodium falciparum–specific IL10 CD4 T cells and protection from malaria in children in an area of high malaria transmission. Front. Immunol. 8:1329
    [Google Scholar]
  112. 112. 
    Mbale EW, Moxon CA, Mukaka M, Chagomerana M, Glover S et al. 2016. HIV coinfection influences the inflammatory response but not the outcome of cerebral malaria in Malawian children. J. Infect. 73:189–99
    [Google Scholar]
  113. 113. 
    Freitas do Rosario AP, Langhorne J 2012. T cell–derived IL-10 and its impact on the regulation of host responses during malaria. Int. J. Parasitol. 42:549–55
    [Google Scholar]
  114. 114. 
    Walther M, Tongren JE, Andrews L, Korbel D, King E et al. 2005. Upregulation of TGF-β, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23:287–96
    [Google Scholar]
  115. 115. 
    Minigo G, Woodberry T, Piera KA, Salwati E, Tjitra E et al. 2009. Parasite-dependent expansion of TNF receptor II–positive regulatory T cells with enhanced suppressive activity in adults with severe malaria. PLOS Pathog 5:e1000402
    [Google Scholar]
  116. 116. 
    Jangpatarapongsa K, Chootong P, Sattabongkot J, Chotivanich K, Sirichaisinthop J et al. 2008. Plasmodium vivax parasites alter the balance of myeloid and plasmacytoid dendritic cells and the induction of regulatory T cells. Eur. J. Immunol. 38:2697–705
    [Google Scholar]
  117. 117. 
    Bueno LL, Morais CG, Araujo FF, Gomes JA, Correa-Oliveira R et al. 2010. Plasmodium vivax: induction of CD4+CD25+FoxP3+ regulatory T cells during infection are directly associated with level of circulating parasites. PLOS ONE 5:e9623
    [Google Scholar]
  118. 118. 
    Walther M, Jeffries D, Finney OC, Njie M, Ebonyi A 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:e1000364
    [Google Scholar]
  119. 119. 
    Abel A, Steeg C, Aminkiah F, Addai-Mensah O, Addo M et al. 2018. Differential expression pattern of co-inhibitory molecules on CD4+ T cells in uncomplicated versus complicated malaria. Sci. Rep. 8:4789
    [Google Scholar]
  120. 120. 
    Mackroth MS, Abel A, Steeg C, Schulze Zur Wiesch J, Jacobs T 2016. Acute malaria induces PD1+CTLA4+ effector T cells with cell-extrinsic suppressor function. PLOS Pathog 12:e1005909
    [Google Scholar]
  121. 121. 
    Subramaniam KS, Spaulding E, Ivan E, Mutimura E, Kim RS et al. 2015. The T-cell inhibitory molecule butyrophilin-like 2 is up-regulated in mild Plasmodium falciparum infection and is protective during experimental cerebral malaria. J. Infect. Dis. 212:1322–31
    [Google Scholar]
  122. 122. 
    Porto BN, Alves LS, Fernandez PL, Dutra TP, Figueiredo RT et al. 2007. Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J. Biol. Chem. 282:24430–36
    [Google Scholar]
  123. 123. 
    Pamplona A, Ferreira A, Balla J, Jeney V, Balla G et al. 2007. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat. Med. 13:703–10
    [Google Scholar]
  124. 124. 
    Walther M, De Caul A, Aka P, Njie M, Amambua-Ngwa A et al. 2012. HMOX1 gene promoter alleles and high HO-1 levels are associated with severe malaria in Gambian children. PLOS Pathog 8:e1002579
    [Google Scholar]
  125. 125. 
    Takeda M, Kikuchi M, Ubalee R, Na-Bangchang K, Ruangweerayut R et al. 2005. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to cerebral malaria in Myanmar. Jpn. J. Infect. Dis. 58:268–71
    [Google Scholar]
  126. 126. 
    Sambo MR, Trovoada MJ, Benchimol C, Quinhentos V, Goncalves L et al. 2010. Transforming growth factor beta 2 and heme oxygenase 1 genes are risk factors for the cerebral malaria syndrome in Angolan children. PLOS ONE 5:e11141
    [Google Scholar]
  127. 127. 
    Hansson HH, Maretty L, Balle C, Goka BQ, Luzon E et al. 2015. Polymorphisms in the Haem Oxygenase-1 promoter are not associated with severity of Plasmodium falciparum malaria in Ghanaian children. Malar. J. 14:153
    [Google Scholar]
  128. 128. 
    Cunnington AJ, Njie M, Correa S, Takem EN, Riley EM, Walther M 2012. Prolonged neutrophil dysfunction after Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-1 induction. J. Immunol. 189:5336–46
    [Google Scholar]
  129. 129. 
    Mooney JP, Galloway LJ, Riley EM 2018. Malaria, anemia, and invasive bacterial disease: a neutrophil problem?. J. Leukoc. Biol. 105:645–55
    [Google Scholar]
  130. 130. 
    Doolan DL, Dobaño C, Baird JK 2009. Acquired immunity to malaria. Clin. Microbiol. Rev. 22:13–36
    [Google Scholar]
  131. 131. 
    Goncalves BP, Huang CY, Morrison R, Holte S, Kabyemela E et al. 2014. Parasite burden and severity of malaria in Tanzanian children. N. Engl. J. Med. 370:1799–808
    [Google Scholar]
  132. 132. 
    Bull PC, Lowe BS, Kortok M, Molyneux CS, Newbold CI, Marsh K 1998. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat. Med. 4:358–60
    [Google Scholar]
  133. 133. 
    Jensen AT, Magistrado P, Sharp S, Joergensen L, Lavstsen T et al. 2004. Plasmodium falciparum associated with severe childhood malaria preferentially expresses PfEMP1 encoded by group A var genes. J. Exp. Med. 199:1179–90
    [Google Scholar]
  134. 134. 
    Chan JA, Fowkes FJ, Beeson JG 2014. Surface antigens of Plasmodium falciparum-infected erythrocytes as immune targets and malaria vaccine candidates. Cell. Mol. Life Sci. 71:3633–57
    [Google Scholar]
  135. 135. 
    Leech JH, Barnwell JW, Miller LH, Howard RJ 1984. Identification of a strain-specific malarial antigen exposed on the surface of Plasmodium falciparum–infected erythrocytes. J. Exp. Med. 159:1567–75
    [Google Scholar]
  136. 136. 
    Silamut K, Phu NH, Whitty C, Turner GD, Louwrier K et al. 1999. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am. J. Pathol. 155:395–410
    [Google Scholar]
  137. 137. 
    Marsh K, Howard RJ. 1986. Antigens induced on erythrocytes by P. falciparum: expression of diverse and conserved determinants. Science 231:150–53
    [Google Scholar]
  138. 138. 
    Chan JA, Howell KB, Reiling L, Ataide R, Mackintosh CL et al. 2012. Targets of antibodies against Plasmodium falciparum–infected erythrocytes in malaria immunity. J. Clin. Investig. 122:3227–38
    [Google Scholar]
  139. 139. 
    Smith JD, Chitnis CE, Craig AG, Roberts DJ, Hudson-Taylor DE et al. 1995. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82:101–10
    [Google Scholar]
  140. 140. 
    Baruch DI, Ma XC, Singh HB, Bi X, Pasloske BL, Howard RJ 1997. Identification of a region of PfEMP1 that mediates adherence of Plasmodium falciparum infected erythrocytes to CD36: conserved function with variant sequence. Blood 90:3766–75
    [Google Scholar]
  141. 141. 
    Smith JD, Craig AG, Kriek N, Hudson-Taylor D, Kyes S et al. 2000. Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: a parasite adhesion trait implicated in cerebral malaria. PNAS 97:1766–71
    [Google Scholar]
  142. 142. 
    Fried M, Duffy PE. 1996. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 272:1502–4
    [Google Scholar]
  143. 143. 
    Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP et al. 2003. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A–adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol. Microbiol. 49:179–91
    [Google Scholar]
  144. 144. 
    Fried M, Nosten F, Brockman A, Brabin BJ, Duffy PE 1998. Maternal antibodies block malaria. Nature 395:851–52
    [Google Scholar]
  145. 145. 
    Ricke CH, Staalsoe T, Koram K, Akanmori BD, Riley EM et al. 2000. Plasma antibodies from malaria-exposed pregnant women recognize variant surface antigens on Plasmodium falciparum–infected erythrocytes in a parity-dependent manner and block parasite adhesion to chondroitin sulfate A. J. Immunol. 165:3309–16
    [Google Scholar]
  146. 146. 
    Fried M, Duffy PE. 2015. Designing a VAR2CSA-based vaccine to prevent placental malaria. Vaccine 33:7483–88
    [Google Scholar]
  147. 147. 
    Mordmuller B, Sulyok M, Egger-Adam D, Resende M, de Jongh WA et al. 2019. First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria. Clin. Infect. Dis 69:1509–16
    [Google Scholar]
  148. 148. 
    Srivastava A, Gangnard S, Dechavanne S, Amirat F, Lewit Bentley A et al. 2011. Var2CSA minimal CSA binding region is located within the N-terminal region. PLOS ONE 6:e20270
    [Google Scholar]
  149. 149. 
    Srivastava A, Gangnard S, Round A, Dechavanne S, Juillerat A et al. 2010. Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA. PNAS 107:4884–89
    [Google Scholar]
  150. 150. 
    Clausen TM, Christoffersen S, Dahlback M, Langkilde AE, Jensen KE et al. 2012. Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate A in placental malaria. J. Biol. Chem. 287:23332–45
    [Google Scholar]
  151. 151. 
    Bigey P, Gnidehou S, Doritchamou J, Quiviger M, Viwami F et al. 2011. The NTS–DBL2X region of VAR2CSA induces cross-reactive antibodies that inhibit adhesion of several Plasmodium falciparum isolates to chondroitin sulfate A. J. Infect. Dis. 204:1125–33
    [Google Scholar]
  152. 152. 
    Higgins MK. 2008. The structure of a chondroitin sulfate-binding domain important in placental malaria. J. Biol. Chem. 283:21842–46
    [Google Scholar]
  153. 153. 
    Singh K, Gittis AG, Nguyen P, Gowda DC, Miller LH, Garboczi DN 2008. Structure of the DBL3x domain of pregnancy-associated malaria protein VAR2CSA complexed with chondroitin sulfate A. Nat. Struct. Mol. Biol. 15:932–38
    [Google Scholar]
  154. 154. 
    Gangnard S, Lewit-Bentley A, Dechavanne S, Srivastava A, Amirat F et al. 2015. Structure of the DBL3X–DBL4ε region of the VAR2CSA placental malaria vaccine candidate: insight into DBL domain interactions. Sci. Rep. 5:14868
    [Google Scholar]
  155. 155. 
    Salanti A, Clausen TM, Agerbaek MO, Al Nakouzi N, Dahlback M et al. 2015. Targeting human cancer by a glycosaminoglycan binding malaria protein. Cancer Cell 28:500–14
    [Google Scholar]
  156. 156. 
    Ayres Pereira M, Mandel Clausen T, Pehrson C, Mao Y, Resende M et al. 2016. Placental sequestration of Plasmodium falciparum malaria parasites is mediated by the interaction between VAR2CSA and chondroitin sulfate A on syndecan-1. PLOS Pathog 12:e1005831
    [Google Scholar]
  157. 157. 
    Lavstsen T, Turner L, Saguti F, Magistrado P, Rask TS et al. 2012. Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. PNAS 109:E1791–800
    [Google Scholar]
  158. 158. 
    Avril M, Tripathi AK, Brazier AJ, Andisi C, Janes JH et al. 2012. A restricted subset of var genes mediates adherence of Plasmodium falciparum–infected erythrocytes to brain endothelial cells. PNAS 109:E1782–90
    [Google Scholar]
  159. 159. 
    Claessens A, Adams Y, Ghumra A, Lindergard G, Buchan CC et al. 2012. A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells. PNAS 109:E1772–81
    [Google Scholar]
  160. 160. 
    Storm J, Jespersen JS, Seydel KB, Szestak T, Mbewe M et al. 2019. Cerebral malaria is associated with differential cytoadherence to brain endothelial cells. EMBO Mol. Med. 11:e9164
    [Google Scholar]
  161. 161. 
    Esmon CT, Ding W, Yasuhiro K, Gu JM, Ferrell G et al. 1997. The protein C pathway: new insights. Thromb. Haemost. 78:70–74
    [Google Scholar]
  162. 162. 
    Gillrie MR, Avril M, Brazier AJ, Davis SP, Stins MF et al. 2015. Diverse functional outcomes of Plasmodium falciparum ligation of EPCR: potential implications for malarial pathogenesis. Cell. Microbiol. 17:1883–99
    [Google Scholar]
  163. 163. 
    Sampath S, Brazier AJ, Avril M, Bernabeu M, Vigdorovich V et al. 2015. Plasmodium falciparum adhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor. Cell. Microbiol. 17:1868–82
    [Google Scholar]
  164. 164. 
    Lennartz F, Adams Y, Bengtsson A, Olsen RW, Turner L et al. 2017. Structure-guided identification of a family of dual receptor-binding PfEMP1 that is associated with cerebral malaria. Cell Host Microbe 21:403–14
    [Google Scholar]
  165. 165. 
    Laszik Z, Mitro A, Taylor FB Jr, Ferrell G, Esmon CT 1997. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 96:3633–40
    [Google Scholar]
  166. 166. 
    Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS et al. 2001. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N. Engl. J. Med. 345:408–16
    [Google Scholar]
  167. 167. 
    Azasi Y, Lindergard G, Ghumra A, Mu J, Miller LH, Rowe JA 2018. Infected erythrocytes expressing DC13 PfEMP1 differ from recombinant proteins in EPCR-binding function. PNAS 115:1063–68
    [Google Scholar]
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