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Genetic analysis of cerebral malaria in the mouse model infected with Plasmodium berghei

Abstract

Malaria is a common and sometimes fatal disease caused by infection with Plasmodium parasites. Cerebral malaria (CM) is a most severe complication of infection with Plasmodium falciparum parasites which features a complex immunopathology that includes a prominent neuroinflammation. The experimental mouse model of cerebral malaria (ECM) induced by infection with Plasmodium berghei ANKA has been used abundantly to study the role of single genes, proteins and pathways in the pathogenesis of CM, including a possible contribution to neuroinflammation. In this review, we discuss the Plasmodium berghei ANKA infection model to study human CM, and we provide a summary of all host genetic effects (mapped loci, single genes) whose role in CM pathogenesis has been assessed in this model. Taken together, the reviewed studies document the many aspects of the immune system that are required for pathological inflammation in ECM, but also identify novel avenues for potential therapeutic intervention in CM and in diseases which feature neuroinflammation.

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References

  1. Alferink J, Specht S, Arends H et al (2016) Cannabinoid receptor 2 modulates susceptibility to experimental cerebral malaria through a CCL17-dependent Mechanism. J Biol Chem 291:19517–19531. https://doi.org/10.1074/jbc.M116.746594

  2. Amani V, Vigário AM, Belnoue E, et al (2000) Involvement of IFN-γ receptor-mediated signaling in pathology and anti-malarial immunity induced by Plasmodium berghei infection. Eur J Immunol 30:1646–1655

  3. Amante FH, Haque A, Stanley AC et al (2010) Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria. J Immunol 185:3632–3642. https://doi.org/10.4049/jimmunol.1000944

  4. Baccarella A, Huang BW, Fontana MF, Kim CC (2014) Loss of Toll-like receptor 7 alters cytokine production and protects against experimental cerebral malaria. Malar J 13:1–8. https://doi.org/10.1186/1475-2875-13-354

  5. Bagot S, Campino S, Penha-Gonçalves C et al (2002) Identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain. Proc Natl Acad Sci U S A 99:9919–9923. https://doi.org/10.1073/pnas.152215199

  6. Bagot S, Nogueira F, Collette A et al (2004) Comparative study of brain CD8 + T cells induced by sporozoites and those induced by blood-stage Plasmodium berghei ANKA involved in the development of cerebral malaria. Infect Immun 72:2817–2826. https://doi.org/10.1128/IAI.72.5.2817

  7. Ball EA, Sambo MR, Martins M et al (2013) IFNAR1 controls progression to cerebral malaria in children and CD8+ T Cell brain pathology in Plasmodium berghei-infected mice. J Immunol 190:5118–5127. https://doi.org/10.4049/jimmunol.1300114

  8. Band G, Le QS, Jostins L et al (2013) Imputation-based meta-analysis of severe malaria in three african populations. PLoS Genet 9:e1003509. https://doi.org/10.1371/journal.pgen.1003509

  9. Band G, Rockett KA, Spencer CCA et al (2015) A novel locus of resistance to severe malaria in a region of ancient balancing selection. Nature 526:253–257. https://doi.org/10.1038/nature15390

  10. Barbosa MDFS., Nguyen QA, Tchernev VT et al (1996) Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature 382:262–265. https://doi.org/10.1038/382262a0

  11. Beghdadi W, Porcherie A, Schneider BS et al (2008) Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease. J Exp Med 205:395–408. https://doi.org/10.1084/jem.20071548

  12. Beghdadi W, Porcherie A, Schneider BS et al (2009) Histamine H3 receptor-mediated signaling protects mice from cerebral malaria. PLoS ONE 4:. https://doi.org/10.1371/journal.pone.0006004

  13. Belnoue E, Kayibanda M, Vigario AM et al (2002) On the pathogenic role of brain-sequestered CD8+ T cells in experimental cerebral malaria. J Immunol 169:6369–6375. https://doi.org/10.4049/jimmunol.169.11.6369

  14. Belnoue E, Costa F, Vigário A et al (2003a) Chemokine receptor CCR2 is not essential for the development of experimental cerebral malaria. Infect Immun 71:3648. https://doi.org/10.1128/IAI.71.6.3648

  15. Belnoue E, Kayibanda M, Deschemin JC et al (2003b) CCR5 deficiency decreases susceptibility to experimental cerebral malaria. Blood 101:4253–4259. https://doi.org/10.1182/blood-2002-05-1493

  16. Belnoue E, Potter SM, Rosa DS et al (2008) Control of pathogenic CD8 + T cell migration to the brain by IFN-γ during experimental cerebral malaria. Parasite Immunol 30:544–553. https://doi.org/10.1111/j.1365-3024.2008.01053.x

  17. Berghout J, Min-Oo G, Tam M et al (2010) Identification of a novel cerebral malaria susceptibility locus (Berr5) on mouse chromosome 19. Genes Immun 11:310–318. https://doi.org/10.1038/gene.2009.79

  18. Berghout J, Langlais D, Radovanovic I et al (2013) Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria. PLoS Pathog 9:e1003491. https://doi.org/10.1371/journal.ppat.1003491

  19. Betz RC, Petukhova L, Ripke S et al (2015) Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci. Nat Commun 6:1–8. https://doi.org/10.1038/ncomms6966

  20. Bongfen SE, Laroque A, Berghout J, Gros P (2009) Genetic and genomic analyses of host-pathogen interactions in malaria. Trends Parasitol 25:417–422

  21. Bongfen SE, Rodrigue-Gervais IG, Berghout J et al (2012) An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria. PLoS ONE 7:e31012. https://doi.org/10.1371/journal.pone.0031012

  22. Bopp SER, Ramachandran V, Henson K et al (2010) Genome wide analysis of inbred mouse lines identifies a locus containing ppar-γ as contributing to enhanced malaria survival. PLoS ONE 5:e10903. https://doi.org/10.1371/journal.pone.0010903

  23. Bopp SE, Rodrigo E, González-Páez GE et al (2013) Identification of the Plasmodium berghei resistance locus 9 linked to survival on chromosome 9. Malar J 12:316. https://doi.org/10.1186/1475-2875-12-316

  24. Boubou MI, Collette A, Voegtlé D et al (1999) T cell response in malaria pathogenesis: Selective increase in T cells carrying the TCR V(β)8 during experimental cerebral malaria. Int Immunol 11:1553–1562. https://doi.org/10.1093/intimm/11.9.1553

  25. Brant F, Miranda AS, Esper L et al (2014) Role of the aryl hydrocarbon receptor in the immune response profile and development of pathology during Plasmodium berghei Anka infection. Infect Immun 82:3127–3140. https://doi.org/10.1128/IAI.01733-14

  26. Brant F, Miranda AS, Esper L et al (2016) Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria. Brain Behav Immun 54:73–85. https://doi.org/10.1016/j.bbi.2016.01.002

  27. Brockmeyer C, Paster W, Pepper D et al (2011) T cell receptor (TCR)-induced tyrosine phosphorylation dynamics identifies THEMIS as a new TCR signalosome component. J Biol Chem 286:7535–7547. https://doi.org/10.1074/jbc.M110.201236

  28. Bullen DVR, Hansen DS, Siomos MAV et al (2003) The lack of suppressor of cytokine signalling-1 (SOCS1) protects mice from the development of cerebral malaria caused by Plasmodium berghei ANKA. Parasite Immunol 25:113–118. https://doi.org/10.1046/j.1365-3024.2003.00616.x

  29. Caignard G, Eva MM, Van Bruggen R et al (2014) Mouse ENU mutagenesis to understand immunity to infection: methods, selected examples, and perspectives. Genes (Basel) 5:887–925

  30. Campanella GSV, Tager AM, El Khoury JK 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 105:4814–4819. https://doi.org/10.1073/pnas.0801544105

  31. Campino S, Bagot S, Bergman ML et al (2005) Genetic control of parasite clearance leads to resistance to Plasmodium berghei ANKA infection and confers immunity. Genes Immun 6:416–421. https://doi.org/10.1038/sj.gene.6364219

  32. Candotti BF, Oakes SA, Johnston JA et al (1997) Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood 90:3996–4003

  33. Chang WL, Li J, Sun G et al (2003) P-selectin contributes to severe experimental malaria but is not required for leukocyte adhesion to brain microvasculature. Infect Immun 71:1911–1918. https://doi.org/10.1128/IAI.71.4.1911-1918.2003

  34. Clark IA, Budd AC, Alleva LM, Cowden WB (2006) Human malarial disease: a consequence of inflammatory cytokine release. Malar J 5:85. https://doi.org/10.1186/1475-2875-5-85

  35. Claser C, Malleret B, Gun SY et al (2011) CD8 + T cells and IFN-γ mediate the time-dependent accumulation of infected red blood cells in deep organs during experimental cerebral malaria. PLoS ONE 6:e18720. https://doi.org/10.1371/journal.pone.0018720

  36. Coban C, Ishii KJ, Uematsu S et al (2007) Pathological role of Toll-like receptor signaling in cerebral malaria. Int Immunol 19:67–79. https://doi.org/10.1093/intimm/dxl123

  37. Combes V, Rosenkranz AR, Redard M et al (2004) Pathogenic role of P-selectin in experimental cerebral malaria: importance of the endothelial compartment. Am J Pathol 164:781–786. https://doi.org/10.1016/S0002-9440(10)63166-5

  38. Combes V, Coltel N, Alibert M et al (2005) ABCA1 Gene Deletion Protects against Cerebral Malaria. Am J Pathol 166:295–302. https://doi.org/10.1016/S0002-9440(10)62253-5

  39. Cowman AF, Crabb BS (2006) Invasion of red blood cells by malaria parasites. Cell 124:755–766

  40. Cox FE (2010) History of the discovery of the malaria parasites and their vectors. Parasites Vectors 3:5

  41. Craig AG, Grau GE, Janse C et al (2012) The role of animal models for research on severe malaria. PLoS Pathog 8:e1002401. https://doi.org/10.1371/journal.ppat.1002401

  42. Cunha-Rodrigues M, Portugal S, Febbraio M, Mota MM (2006) Infection by and protective immune responses against Plasmodium berghei ANKA are not affected in macrophage scavenger receptors A deficient mice. BMC Microbiol 6:1–5. https://doi.org/10.1186/1471-2180-6-73

  43. Darley MM, Ramos TN, Wetsel RA, Barnum SR (2012) Deletion of carboxypeptidase N delays onset of experimental cerebral malaria. Parasite Immunol 34:444–447. https://doi.org/10.1111/j.1365-3024.2012.01376.x

  44. De Souza J, Riley E (2002) Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis. Microbes Infect 4:291–300

  45. De Souza J, Hafalla J, Riley E, Couper K (2010) Cerebral malaria: Why experimental murine models are required to understand the pathogenesis of disease. Parasitology 137:755–772

  46. Dondorp AM, Kager PA, Vreeken J, White NJ (2000) Abnormal blood flow and red blood cell deformability in severe malaria. Parasitol Today 16:228–232. https://doi.org/10.1016/S0169-4758(00)01666-5

  47. Dostert C, Guarda G, Romero JF et al (2009) Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One 4:1–10. https://doi.org/10.1371/journal.pone.0006510

  48. Driss A, Hibbert JM, Wilson NO et al (2011) Genetic polymorphisms linked to susceptibility to malaria. Malar J 10:271. https://doi.org/10.1186/1475-2875-10-271

  49. Dubois PCA, Trynka G, Franke L et al (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42:295–302. https://doi.org/10.1038/ng.543

  50. Dunst J, Kamena F, Matuschewski K (2017) Cytokines and Chemokines in Cerebral Malaria Pathogenesis. Front Cell Infect Microbiol 7:. https://doi.org/10.3389/fcimb.2017.00324

  51. Edwards CL, Best SE, Gun SY et al (2015) Spatiotemporal requirements for IRF7 in mediating type I IFN-dependent susceptibility to blood-stage Plasmodium infection. Eur J Immunol 45:130–141. https://doi.org/10.1002/eji.201444824

  52. El-Assaad F, Wheway J, Mitchell AJ et al (2013) Cytoadherence of plasmodium berghei-infected red blood cells to murine brain and lung microvascular endothelial cells in vitro. Infect Immun 81:3984–3991. https://doi.org/10.1128/IAI.00428-13

  53. El-Assaad F, Combes V, Grau GE (2014) Experimental models of microvascular immunopathology: the example of cerebral malaria. J Neuroinfect Dis 2:92–94. https://doi.org/10.14440/jbm.2015.54.A

  54. Ellinghaus D, Ellinghaus E, Nair RP et al (2012) Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet 90:636–647. https://doi.org/10.1016/j.ajhg.2012.02.020

  55. Elphinstone RE, Besla R, Shikatani EA et al (2017) S-Nitrosoglutathione reductase deficiency confers improved survival and neurological outcome in experimental cerebral malaria. Infect Immun 85:1–12. https://doi.org/10.1128/IAI.00371-17

  56. Engelhardt KR, McGhee S, Winkler S et al (2009) Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 124:. https://doi.org/10.1016/j.jaci.2009.10.038

  57. Engwerda CR, Mynott TL, Sawhney S et al (2002) Locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principle mediator of murine cerebral malaria. J Exp Med 195:1371–1377. https://doi.org/10.1084/jem.20020128

  58. Engwerda C, Belnoue E, Gruner AC, Renia L (2005) Experimental models of cerebral malaria. Curr Top Microbiol Immunol 297:103–143

  59. Everitt AR, Clare S, McDonald JU et al (2013) Defining the range of pathogens susceptible to ifitm3 restriction using a knockout mouse model. PLoS One 8:1–12. https://doi.org/10.1371/journal.pone.0080723

  60. Fauconnier M, Bourigault M-L, Meme S et al (2011) Protein kinase C-Theta is required for development of experimental cerebral malaria. Am J Pathol 178:212–221. https://doi.org/10.1016/j.ajpath.2010.11.008

  61. Fauconnier M, Palomo J, Bourigault M-L et al (2012) IL-12R 2 Is essential for the development of experimental cerebral malaria. J Immunol 188:1905–1914. https://doi.org/10.4049/jimmunol.1101978

  62. Favre N, Da Laperousaz C, Ryffel B et al (1999a) Role of ICAM-1 (CD54) in the development of murine cerebral malaria. Microbes Infect 1:961–968. https://doi.org/10.1016/S1286-4579(99)80513-9

  63. Favre N, Ryffel B, Rudin W (1999b) The development of murine cerebral malaria does not require nitric oxide production. Parasitology 118:135–138. https://doi.org/10.1017/S0031182098003606

  64. Fodil N, Moradin N, Leung V et al (2017) CCDC88B is required for pathogenesis of inflammatory bowel disease. Nat Commun 8:1–12. https://doi.org/10.1038/s41467-017-01381-y

  65. Frank J, Pignata C, Panteleyev AA et al (1999) Exposing the human nude phenotype. Nature 398:473–474. https://doi.org/10.1038/18997

  66. Franke-Fayard B, Janse CJ, Cunha-Rodrigues M et al (2005) From the cover: murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration. Proc Natl Acad Sci 102:11468–11473. https://doi.org/10.1073/pnas.0503386102

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

  68. Goldman FD, Ballas ZK, Schutte BC et al (1998) Defective p56lck expression in an Infant with SCID defective expression of p56lck in an infant with severe combined immunodeficiency. J Clin Invest 102:421–429. https://doi.org/10.1172/JCI3205

  69. Gramaglia I, Sobolewski P, Meays D et al (2006) Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med 12:1417–1422. https://doi.org/10.1038/nm1499

  70. Griffith JW, O’Connor C, Bernard K et al (2007) Toll-like receptor modulation of murine cerebral malaria is dependent on the genetic background of the host. J Infect Dis 196:1553–1564. https://doi.org/10.1086/522865

  71. Guo J, McQuillan JA, Yau B et al (2015) IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria. Infect Immun 83:1406–1417. https://doi.org/10.1128/IAI.02701-14

  72. Ham H, Huynh W, Schoon R et al (2015) HkRP3 Is a microtubule-binding protein regulating lytic granule clustering and NK cell killing. J Immunol 194:3984–3996. https://doi.org/10.4049/jimmunol.1402897

  73. Hansen DS (2012) Inflammatory responses associated with the induction of cerebral malaria: lessons from experimental murine models. PLoS Pathog 8:e1003045. https://doi.org/10.1371/journal.ppat.1003045

  74. Hansen DS, Siomos MA, Buckingham L et al (2003) Regulation of murine cerebral malaria pathogenesis by CD1d-restricted NKT cells and the natural killer complex. Immunity 18:391–402. https://doi.org/10.1016/S1074-7613(03)00052-9

  75. Haque A, Best SE, Unosson K et al (2011) Granzyme B Expression by CD8 + T Cells Is Required for the Development of Experimental Cerebral Malaria. J Immunol 186:6148–6156. https://doi.org/10.4049/jimmunol.1003955

  76. Hearn J, Rayment N, Landon DN et al (2000) Immunopathology of cerebral malaria: Morphological evidence of parasite sequestration in murine brain microvasculature. Infect Immun 68:5364–5376. https://doi.org/10.1128/IAI.68.9.5364-5376.2000

  77. Hempel C, Combes V, Hunt NH et al (2011) CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and is reversed by erythropoietin. Am J Pathol 179:1939–1950. https://doi.org/10.1016/j.ajpath.2011.06.027

  78. Herbas MS, Okazaki M, Terao E et al (2010) a-Tocopherol transfer protein inhibition is effective in the prevention of cerebral malaria in mice 1–3. 200–207. https://doi.org/10.3945/ajcn.2009.28260.200

  79. Hernandez-Valladares M, Rihet P, Iraqi FA (2014) Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes. Physiol Genomics 46:1–16. https://doi.org/10.1152/physiolgenomics.00044.2013

  80. Hiller NL, Bhattacharjee S, Van Ooij C et al (2004) A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306:1934–1937. https://doi.org/10.1126/science.1102737

  81. Hora R, Kapoor P, Thind KK, Mishra PC (2016) Cerebral malaria – clinical manifestations and pathogenesis. Metab Brain Dis 31:225–237. https://doi.org/10.1007/s11011-015-9787-5

  82. Howland SW, Claser C, Poh CM et al (2015) Pathogenic CD8 + T cells in experimental cerebral malaria. Semin Immunopathol 37:221–231. https://doi.org/10.1007/s00281-015-0476-6

  83. Hulden L, Hulden L, Hay S et al (2011) Activation of the hypnozoite: a part of Plasmodium vivax life cycle and survival. Malar J 10:90. https://doi.org/10.1186/1475-2875-10-90

  84. Hunt NH, Grau GE (2003a) Cytokines: Accelerators and brakes in the pathogenesis of cerebral malaria. Trends Immunol 24:491–499. https://doi.org/10.1016/S1471-4906(03)00229-1

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

  86. Hunt NH, Driussi C, Sai-Kiang L (2001) Haptoglobin and malaria. Redox Rep 6:389–392. https://doi.org/10.1179/135100001101536508

  87. Hunt NH, Golenser J, Chan-Ling T et al (2006) Immunopathogenesis of cerebral malaria. Int J Parasitol 36:569–582

  88. Ioannidis LJ, Nie CQ, Ly A et al (2016) Monocyte- and neutrophil-derived CXCL10 Impairs efficient control of blood-stage malaria infection and promotes severe disease. J Immunol 196:1227–1238. https://doi.org/10.4049/jimmunol.1501562

  89. Ishida H, Matsuzaki-Moriya C, Imai T et al (2010) Development of experimental cerebral malaria is independent of IL-23 and IL-17. Biochem Biophys Res Commun 402:790–795. https://doi.org/10.1016/j.bbrc.2010.10.114

  90. Ishikawa S, Uozumi N, Shiibashi T et al (2004) Short report: Lethal malaria in cytosolic phospholipase A2- and phospholipase A2IIA-deficient mice. Am J Trop Med Hyg 70:645–650

  91. Jallow M, Teo YY, Small KS et al (2009) Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet 41:657–665. https://doi.org/10.1038/ng.388

  92. Jamison DT, Feachem RG, Makgoba MW et al (2006) Disease and Mortality in Sub-Saharan Africa. The International Bank for Reconstruction and Development/The World Bank, Washington (DC)

  93. Jostins L, Ripke S, Weersma RK et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124. https://doi.org/10.1038/nature11582

  94. Kain KC, Yeh W-C, Liles WC et al (2010) Divergent Roles of IRAK4-Mediated Innate Immune Responses in Two Experimental Models of Severe Malaria. Am J Trop Med Hyg 83:69–74. https://doi.org/10.4269/ajtmh.2010.09-0753

  95. Kassa FA, Van Den Ham K, Rainone A et al (2016) Absence of apolipoprotein e protects mice from cerebral malaria. Sci Rep 6:1–13. https://doi.org/10.1038/srep33615

  96. Kennedy JM, Fodil N, Torre S et al (2014) CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation. J Exp Med 211:2519–2535. https://doi.org/10.1084/jem.20140455

  97. Kim H, Erdman LK, Lu Z et al (2014) Functional roles for C5a and C5aR but not C5L2 in the pathogenesis of human and experimental cerebral malaria. Infect Immun 82:371–379. https://doi.org/10.1128/IAI.01246-13

  98. Kordes M, Matuschewski K, Hafalla JCR (2011) Caspase-1 activation of interleukin-1β (IL-1β) And IL-18 Is Dispensable for Induction of Experimental Cerebral Malaria. Infect Immun 79:3633–3641. https://doi.org/10.1128/IAI.05459-11

  99. Kwiatkowski DP (2005) How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77:171–192. https://doi.org/10.1086/432519

  100. Labbe K, Miu J, Yeretssian G et al (2010) Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF- B signaling. J Immunol 185:5495–5502. https://doi.org/10.4049/jimmunol.1002517

  101. Lacerda-Queiroz N, Rodrigues DH, Vilela MC et al (2012) Platelet-activating factor receptor is essential for the development of experimental cerebral malaria. Ajpa 180:246–255. https://doi.org/10.1016/j.ajpath.2011.09.038

  102. Lacerda-Queiroz N, Brant F, Rodrigues DH et al (2015) Phosphatidylinositol 3-kinase ? is required for the development of experimental cerebral malaria. PLoS ONE 10:1–13. https://doi.org/10.1371/journal.pone.0119633

  103. Lambert JC, Ibrahim-Verbaas C, Harold D et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. https://doi.org/10.1038/ng.2802

  104. Langhorne J, Buffet P, Galinski M et al (2011) The relevance of non-human primate and rodent malaria models for humans. Malar J 10:23

  105. Langlais D, Fodil N, Gros P (2017) Genetics of infectious and inflammatory diseases: overlapping discoveries from association and exome-sequencing studies. Annu Rev Immunol 35:1–30. https://doi.org/10.1146/annurev-immunol-051116-052442

  106. Leitner WW, Bergmann-Leitner ES, Angov E (2010) Comparison of Plasmodium berghei challenge models for the evaluation of pre-erythrocytic malaria vaccines and their effect on perceived vaccine efficacy. Malar J 9:145. https://doi.org/10.1186/1475-2875-9-145

  107. Lelliott PM, McMorran BJ, Foote SJ, Burgio G (2015) The influence of host genetics on erythrocytes and malaria infection: Is there therapeutic potential? Malar J 14:289

  108. Li J, Chang W-L, Sun G et al (2003) Intercellular adhesion molecule 1 is important for the development of severe experimental malaria but is not required for leukocyte adhesion in the brain. J Investig Med 51:128–140. https://doi.org/10.1136/jim-51-03-15

  109. Liehl P, Zuzarte-Luís V, Chan J et al (2014) Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection. Nat Med 20:47–53. https://doi.org/10.1038/nm.3424

  110. Lindblade KA, Steinhardt L, Samuels A et al (2013) The silent threat: asymptomatic parasitemia and malaria transmission. Expert Rev Anti Infect Ther 11:623–639. https://doi.org/10.1586/eri.13.45

  111. Longley R, Smith C, Fortin A et al (2011) Host resistance to malaria: using mouse models to explore the host response. Mamm Genome 22:32–42. https://doi.org/10.1007/s00335-010-9302-6

  112. Lou J, Lucas R, Grau GE (2001) Pathogenesis of cerebral malaria: Recent experimental data and possible applications for humans. Clin Microbiol Rev 14:810–820

  113. Lu Z, Serghides L, Patel SN et al (2006) Disruption of JNK2 decreases the cytokine response to Plasmodium falciparum glycosylphosphatidylinositol in vitro and confers protection in a cerebral malaria model. J Immunol 177:6344–6352. https://doi.org/10.4049/jimmunol.177.9.6344

  114. Lucas R, Juillard P, Decoster E et al (1997) Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria. Eur J Immunol 27:1719–1725. https://doi.org/10.1002/eji.1830270719

  115. MacKintosh CL, Beeson JG, Marsh K (2004) Clinical features and pathogenesis of severe malaria. Trends Parasitol 20:597–603

  116. 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 191:2551–2559. https://doi.org/10.4049/jimmunol.1203451

  117. Maitland K (2006) Severe malaria: lessons learned from the management of critical illness in children. Trends Parasitol 22:457–462. https://doi.org/10.1016/j.pt.2006.07.006

  118. Maitland K, Newton CRJC. (2005) Acidosis of severe falciparum malaria: Heading for a shock? Trends Parasitol 21:11–16

  119. Malaria Genomic Epidemiology Network (2014) Reappraisal of known malaria resistance loci in a large multicenter study. Nat Genet 46:1197–1204. https://doi.org/10.1038/ng.3107

  120. Porcherie A, Mathieu C, Peronet R, et al (1894) Two monographs on malaria and the parasites of malarial fevers (translated from the first Italian edition by JH Thompson). New Sydenham Soc, London

  121. Mcmorran BJ, Marshall VM, Graaf C, De et al (2009) Platelets Kill Intraerythrocytic malarial parasites and mediate survival to infection. Science 323:797–800. https://doi.org/10.1126/science.1166296

  122. Medana IM, Chaudhri G, Chan-Ling T, Hunt NH (2001) Central nervous system in cerebral malaria: “Innocent bystander” or active participant in the induction of immunopathology? Immunol. Cell Biol 79:101–120

  123. Mells GF, Floyd JAB, Morley KI et al (2011) Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet 43:1164–1164. https://doi.org/10.1038/ng1111-1164b

  124. Mestas J, Hughes CCW (2004) Of Mice and Not Men: Differences between Mouse and Human Immunology. J Immunol 172:2731–2738. https://doi.org/10.4049/jimmunol.172.5.2731

  125. Miller LH, Baruch DI, Marsh K, Doumbo OK (2002) The pathogenic basis of malaria. Nature 415:673–679

  126. Miller LH, Ackerman HC, Su XZ, Wellems TE (2013) Malaria biology and disease pathogenesis: insights for new treatments. Nat Med 19:156–167. https://doi.org/10.1038/nm.3073

  127. Miller JL, Sack BK, Baldwin M et al (2014) Interferon-mediated innate immune responses against malaria parasite liver stages. Cell Rep 7:436–447. https://doi.org/10.1016/j.celrep.2014.03.018

  128. Mishra SK, Newton CRJC. (2009) Diagnosis and management of the neurological complications of falciparum malaria. Nat Rev Neurol 5:189–198. https://doi.org/10.1038/nrneurol.2009.23

  129. Miu J, Muller MaJ M, et al (2008) Chemokine gene expression during fatal murine cerebral Malaria and protection due to CXCR3 deficiency. J Immunol 180:1217–1230. https://doi.org/10.4049/jimmunol.180.2.1217

  130. Miu J, Ball HJ, Mellor AL, Hunt NH (2009) Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria. Int J Parasitol 39:363–370. https://doi.org/10.1016/j.ijpara.2008.10.005

  131. Miyakoda M, Kimura D, Yuda M et al (2008) Malaria-specific and nonspecific activation of CD8 + T cells during blood stage of Plasmodium berghei infection. J Immunol 181:1420–1428. doi: 181/2/1420 [pii]

  132. Moya-Alvarez V, Abellana R, Cot M (2014) Pregnancy-associated malaria and malaria in infants: An old problem with present consequences. Malar J 13:271

  133. Nagayasu E, Nagakura K, Akaki M et al (2002) Association of a determinant on mouse chromosome 18 with experimental severe Plasmodium berghei malaria. Infect Immun 70:512–516. https://doi.org/10.1128/IAI.70.2.512-516.2002

  134. Nagle DL, Karim MA, Woolf EA et al (1996) Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet 14:307–311. https://doi.org/10.1038/ng1196-307

  135. Nehls M, Pfeifer D, Schorpp M et al (1994) New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372:103–107. https://doi.org/10.1038/372103a0

  136. Newbold C, Warn P, Black G et al (1997) Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am J Trop Med Hyg 57:389–398. https://doi.org/10.1038/nm1297-1315

  137. Nie CQ, Bernard NJ, Norman MU et al (2009) IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection. PLoS Pathog 5:e1000369. https://doi.org/10.1371/journal.ppat.1000369

  138. Nitcheu J, Bonduelle O, Combadiere C et al (2003) Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis. J Immunol 170:2221–2228. https://doi.org/10.4049/jimmunol.170.4.2221

  139. O’regan NO, Gegenbauer K, Sullivan JMO et al (2016) A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria. Blood 127:1192–1202. https://doi.org/10.1182/blood-2015-07-654921

  140. Oakley MS, McCutchan TF, Anantharaman V et al (2008) Host biomarkers and biological pathways that are associated with the expression of experimental cerebral malaria in mice. Infect Immun 76:4518–4529. https://doi.org/10.1128/IAI.00525-08

  141. Oakley MS, Majam V, Mahajan B et al (2009) Pathogenic roles of CD14, galectin-3, and OX40 during experimental cerebral malaria in mice. PLoS One 4:. https://doi.org/10.1371/journal.pone.0006793

  142. Oakley MS, Sahu BR, Lotspeich-Cole L et al (2013) The transcription factor T-bet regulates parasitemia and promotes pathogenesis during Plasmodium berghei ANKA murine malaria. J Immunol 191:4699–4708. https://doi.org/10.4049/jimmunol.1300396

  143. Ohayon A, Golenser J, Sinay R et al (2010) Protein kinase C θ deficiency increases resistance of C57BL/6J mice to Plasmodium berghei infection-induced cerebral malaria. Infect Immun 78:4195–4205. https://doi.org/10.1128/IAI.00465-10

  144. Ohno T, Nishimura M (2004) Detection of a new cerebral malaria susceptibility locus, using CBA mice. Immunogenetics 56:675–678. https://doi.org/10.1007/s00251-004-0739-1

  145. Ohno T, Kobayashi F, Nishimura M (2005) Fas has a role in cerebral malaria, but not in proliferation or exclusion of the murine parasite in mice. Immunogenetics 57:293–296. https://doi.org/10.1007/s00251-005-0791-5

  146. Palomo J, Fauconnier M, Coquard L et al (2013) Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood-stage Plasmodium berghei ANKA. Eur J Immunol 43:2683–2695. https://doi.org/10.1002/eji.201343327

  147. Palomo J, Reverchon F, Piotet J et al (2015) Critical role of IL-33 receptor ST2 in experimental cerebral malaria development. Eur J Immunol 45:1354–1365. https://doi.org/10.1002/eji.201445206

  148. Pamplona A, Ferreira A, Balla J et al (2007) Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13:703–710. https://doi.org/10.1038/nm1586

  149. Patel SN, Berghout J, Lovegrove FE et al (2008) C5 deficiency and C5a or C5aR blockade protects against cerebral malaria. J Exp Med 205:1133–1143. https://doi.org/10.1084/jem.20072248

  150. Pauli EK, Chan YK, Davis ME et al (2014) The ubiquitin-specific protease USP15 promotes RIG-I-mediated antiviral signaling by deubiquitylating TRIM25. Sci Signal 7:ra3. https://doi.org/10.1126/scisignal.2004577

  151. Pignata C, Fiore M, Guzzetta V, et al (1996) Congenital alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs. Am J Med Genet 65:167–170

  152. Piguet PF, Laperrousaz CDA, Tacchini-cottier F et al (2000) Delayed mortality and attenuated thrombocytopenia associated with severe malaria in Urokinase- and Urokinase receptor-deficient mice delayed mortality and attenuated thrombocytopenia associated with severe malaria in Urokinase- and Urokinase receptor-defi. Infect Immun 68:3822–3829. https://doi.org/10.1128/IAI.68.7.3822-3829.2000.Updated

  153. Piguet PF, Kan CD, Vesin C et al (2001) Role of CD40-CVD40L in mouse severe malaria. Am J Pathol 159:733–742. https://doi.org/10.1016/S0002-9440(10)61744-0

  154. Piguet PF, Da Kan C, Vesin C (2002) Role of the tumor necrosis factor receptor 2 (TNFR2) in cerebral malaria in mice. Lab Investig 82:1155–1166. https://doi.org/10.1097/01.LAB.0000028822.94883.8A

  155. Porcherie A, Mathieu C, Peronet R, et al (2011) Critical role of the neutrophil-associated high-affinity receptor for IgE in the pathogenesis of experimental cerebral malaria. J Exp Med 208:2225–2236. https://doi.org/10.1084/jem.20110845

  156. Potter S, Chaudhri G, Hansen A, Hunt NH (1999) Fas and perforin contribute to the pathogenesis of murine cerebral malaria. Redox Rep 4:333–335. https://doi.org/10.1179/135100099101535070

  157. Potter SM, Mitchell AJ, Cowden WB et al (2005) Phagocyte-derived reactive oxygen species do not influence the progression of murine blood-stage malaria infections. Infect Immun 73:4941–4947. https://doi.org/10.1128/IAI.73.8.4941

  158. Potter SM, Chan-Ling T, Rosinova E et al (2006a) A role for Fas-Fas ligand interactions during the late-stage neuropathological processes of experimental cerebral malaria. J Neuroimmunol 173:96–107. https://doi.org/10.1016/j.jneuroim.2005.12.004

  159. Potter S, Chan-Ling T, Ball HJ et al (2006b) Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria. Int J Parasitol 36:485–496. https://doi.org/10.1016/j.ijpara.2005.12.005

  160. Power HJ (2001) History of Malaria. In: Encyclopedia of Life Sciences. Wiley, Chichester

  161. Price RN, Simpson JA, Nosten F et al (2001) Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg 65:614–622

  162. Ramos TN, Darley MM, Hu X et al (2011) Cutting edge: the membrane attack complex of complement is required for the development of murine experimental cerebral malaria. J Immunol 186:6657–6660. https://doi.org/10.4049/jimmunol.1100603

  163. Ramos TN, Bullard DC, Barnum SR (2012a) Deletion of the complement phagocytic receptors CR3 and CR4 does not alter susceptibility to experimental cerebral malaria. Parasite Immunol 34:547–550. https://doi.org/10.1111/pim.12002

  164. Ramos TN, Darley MM, Weckbach S et al (2012b) The C5 convertase is not required for activation of the terminal complement pathway in murine experimental cerebral malaria. J Biol Chem 287:24734–24738. https://doi.org/10.1074/jbc.C112.378364

  165. Ramos TN, Bullard DC, Darley MM et al (2013) Experimental cerebral malaria develops independently of endothelial expression of intercellular adhesion molecule-1 (ICAM-1). J Biol Chem 288:10962–10966. https://doi.org/10.1074/jbc.C113.457028

  166. Reimer T, Shaw MH, Franchi L et al (2010) Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome. Eur J Immunol 40:764–769. https://doi.org/10.1002/eji.200939996

  167. Rest JR (1982) Cerebral malaria in inbred mice. I. A new model and its pathology. Trans R Soc Trop Med Hyg 76:410–415

  168. Reverchon F, Mortaud S, Sivoyon M et al (2017) IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria. PLoS Pathog 13:1–25. https://doi.org/10.1371/journal.ppat.1006322

  169. Riley EM, Couper KN, Helmby H et al (2010) Neuropathogenesis of human and murine malaria. Trends Parasitol 26:277–278

  170. Russell SM, Tayebi N, Nakajima H et al (1995) Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270:797–800. https://doi.org/10.1126/science.270.5237.797

  171. Saeftel M, Krueger A, Arriens S et al (2004) Mice Deficient in Interleukin-4 (IL-4) or IL-4 Receptor α Have Higher Resistance to Sporozoite Infection with Plasmodium berghei (ANKA) than Do Naive Wild-Type Mice. Infect Immun 72:322–331. https://doi.org/10.1128/IAI.72.1.322-331.2004

  172. Sanni LA, Thomas SR, Tattam BN et al (1998) Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria. Am J Pathol 152:611–619

  173. Sanni LA, Fu S, Dean RT et al (1999) Are reactive oxygen species involved in the pathogenesis of murine cerebral malaria? J Infect Dis 179:217–222. https://doi.org/10.1086/314552

  174. Sawcer S, Hellenthal G, Pirinen M et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219. https://doi.org/10.1038/nature10251

  175. Schmid U, Stenzel W, Koschel J et al (2017) The deubiquitinating enzyme cylindromatosis dampens CD8 + T cell responses and is a critical factor for experimental cerebral malaria and blood-brain barrier damage. Front Immunol 8:1–17. https://doi.org/10.3389/fimmu.2017.00027

  176. Schofield L, Grau GE (2005) Immunological processes in malaria pathogenesis. Nat Rev Immunol 5:722–735. https://doi.org/10.1038/nri1686

  177. Sellau J, Alvarado CF, Hoenow S et al (2016) IL-22 dampens the T cell response in experimental malaria. Sci Rep 6:1–11. https://doi.org/10.1038/srep28058

  178. Senaldi G, Shaklee CL, Guo J et al (1999) Protection against the mortality associated with disease models mediated by TNF and IFN-γ in mice lacking IFN regulatory factor-1. J Immunol 163:6820–6826

  179. Sharma S, DeOliveira RB, Kalantari P et al (2011) Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome. Immunity 35:194–207. https://doi.org/10.1016/j.immuni.2011.05.016

  180. Shibui A, Takamori A, Tolba MEM et al (2016) IL-25, IL-33 and TSLP receptor are not critical for development of experimental murine malaria. Biochem Biophys Reports 5:191–195. https://doi.org/10.1016/j.bbrep.2015.12.007

  181. Shryock N, McBerry C, Salazar Gonzalez RM et al (2013) Lipoxin A4 and 15-Epi-Lipoxin A4 protect against experimental cerebral malaria by inhibiting IL-12/IFN-γ in the brain. PLoS ONE 8:2–10. https://doi.org/10.1371/journal.pone.0061882

  182. Srivastava K, Cockburn IA, Swaim A et al (2008) Platelet factor 4 mediates inflammation in experimental cerebral malaria. Cell Host Microbe 4:179–187. https://doi.org/10.1016/j.chom.2008.07.003

  183. Stevenson MM, Gros P, Olivier M et al (2010) Cerebral malaria: human versus mouse studies. Trends Parasitol 26:274–275

  184. Su X, Hayton K, Wellems TE (2007) Genetic linkage and association analyses for trait mapping in Plasmodium falciparum. Nat Rev Genet 8:497–506

  185. Szalai AJ, Barnum SR, Ramos TN (2014) Deletion of C-reactive protein ameliorates experimental cerebral malaria? Trans R Soc Trop Med Hyg 108:591–593. https://doi.org/10.1093/trstmh/tru098

  186. Taylor TE, Borgstein A, Molyneux ME (1993) Acid-base status in paediatric Plasmodium falciparum malaria. Q J Med 86:99–109

  187. Taylor-Robinson AW (2010) Validity of modelling cerebral malaria in mice: argument and counter argument. J Neuroparasitol 1:45–49. https://doi.org/10.4303/jnp/N100601

  188. Timmann C, Thye T, Vens M et al (2012) Genome-wide association study indicates two novel resistance loci for severe malaria. Nature 489:443–446. https://doi.org/10.1038/nature11334

  189. Togbe D, Schofield L, Grau GE et al (2007) Murine cerebral malaria development is independent of toll-like receptor signaling. Am J Pathol 170:1640–1648. https://doi.org/10.2353/ajpath.2007.060889

  190. Togbe D, de Sousa PL, Fauconnier M et al (2008) Both functional LTβ receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. PLoS ONE 3:. https://doi.org/10.1371/journal.pone.0002608

  191. Torre S, Van Bruggen R, Kennedy JM et al (2013) Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice. Genes Immun 14:249–257. https://doi.org/10.1038/gene.2013.16

  192. Torre S, Faucher SP, Fodil N et al (2015) THEMIS Is required for pathogenesis of cerebral malaria and protection against pulmonary tuberculosis. Infect Immun 83:759–768. https://doi.org/10.1128/IAI.02586-14

  193. Torre S, Polyak MJ, Langlais D et al (2017) USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation. Nat Immunol 18:54–63. https://doi.org/10.1038/ni.3581

  194. Trampuz A, Jereb M, Muzlovic I, Prabhu RM (2003) Clinical review: Severe malaria. Crit Care 7:315–323

  195. Van Bruggen R, Gualtieri C, Iliescu A et al (2015) Modulation of malaria phenotypes by pyruvate kinase (pklr) variants in a Thai population. PLoS ONE 10:e0144555. https://doi.org/10.1371/journal.pone.0144555

  196. Van Den Steen PE, Van Aelst I, Starckx S et al (2006) Matrix metalloproteinases, tissue inhibitors of MMPs and TACE in experimental cerebral malaria. Lab Investig 86:873–888. https://doi.org/10.1038/labinvest.3700454

  197. Van Der Heyde HC, Bauer P, Sun G et al (2001) Assessing vascular permeability during experimental cerebral malaria by a radiolabeled monoclonal antibody technique. Infect Immun 69:3460–3465. https://doi.org/10.1128/IAI.69.5.3460-3465.2001

  198. van der Heyde HC, Nolan J, Combes V et al (2006) A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol 22:503–508. https://doi.org/10.1016/j.pt.2006.09.002

  199. Verra F, Mangano VD, Modiano D (2009) Genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome-wide association studies. Parasite Immunol 31:234–253

  200. Villegas-Mendez A, Greig R, Shaw TN et al (2012) IFN-γ-producing CD4+ T Cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain. J Immunol 189:968–979. https://doi.org/10.4049/jimmunol.1200688

  201. Wah ST, Hananantachai H, Kerdpin U et al (2016) Molecular basis of human cerebral malaria development. Trop Med Health 44:2401–2407

  202. Waisberg M, Tarasenko T, Vickers BK et al (2011) Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice. Proc Natl Acad Sci 108:1122–1127. https://doi.org/10.1073/pnas.1017996108

  203. Wassmer SC, Grau GER (2016) Platelets as pathogenetic effectors and killer cells in cerebral malaria. Expert Rev Hematol 9:515–517. https://doi.org/10.1080/17474086.2016.1179571

  204. White NJ, Turner GDH, Medana IM et al (2010) The murine cerebral malaria phenomenon. Trends Parasitol 26:11–15. https://doi.org/10.1016/j.pt.2009.10.007

  205. White NJ, Turner GDH, Day NPJ, Dondorp AM (2013) Lethal malaria: marchiafava and bignami were right. J Infect Dis 208:192–198

  206. White NJ, Pukrittayakamee S, Hien TT et al (2014) Malaria Lancet 383:723–735. https://doi.org/10.1016/S0140-6736(13)60024-0

  207. World Health Organization (2016) World Malaria Report 2016. World Health Organization, Geneva

  208. World Health Organization (2017) World Malaria Report 2017. World Health Organization, Geneva

  209. Yanez DM, Manning DD, Cooley AJ et al (1996) Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria. J Immunol 157:1620–1624

  210. Zhang Q, Davis JC, Lamborn IT et al (2009) Combined immunodeficiency associated with DOCK8 Mutations. N Engl J Med 361:2046–2055. https://doi.org/10.1056/NEJMoa0905506

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Acknowledgements

The work in PG lab was supported by grants to PG from the Canadian Institutes of Health Research, and the Canadian Institute for Advanced Research. PG is endebted to the many trainees in his lab that have contributed to the genetic analysis of susceptibility to malaria in mouse models of infection.

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Correspondence to Philippe Gros.

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Torre, S., Langlais, D. & Gros, P. Genetic analysis of cerebral malaria in the mouse model infected with Plasmodium berghei. Mamm Genome 29, 488–506 (2018). https://doi.org/10.1007/s00335-018-9752-9

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