EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria

Autoři: Thayer K. Darling aff001;  Patrice N. Mimche aff001;  Christian Bray aff002;  Banlanjo Umaru aff003;  Lauren M. Brady aff002;  Colleen Stone aff001;  Carole Else Eboumbou Moukoko aff003;  Thomas E. Lane aff001;  Lawrence S. Ayong aff003;  Tracey J. Lamb aff001
Působiště autorů: Department of Pathology, University of Utah, Salt Lake City, UT, United States of America aff001;  Department of Pediatric Infectious Diseases, Emory University School of Medicine, Atlanta, GA, United States of America aff002;  Malaria Research Unit, Centre Pasteur du Cameroun, Yaoundé, Cameroon aff003;  Department of Biological Sciences, University of Douala, Douala, Cameroon aff004
Vyšlo v časopise: EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008261
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008261


Disruption of blood-brain barrier (BBB) function is a key feature of cerebral malaria. Increased barrier permeability occurs due to disassembly of tight and adherens junctions between endothelial cells, yet the mechanisms governing junction disassembly and vascular permeability during cerebral malaria remain poorly characterized. We found that EphA2 is a principal receptor tyrosine kinase mediating BBB breakdown during Plasmodium infection. Upregulated on brain microvascular endothelial cells in response to inflammatory cytokines, EphA2 is required for the loss of junction proteins on mouse and human brain microvascular endothelial cells. Furthermore, EphA2 is necessary for CD8+ T cell brain infiltration and subsequent BBB breakdown in a mouse model of cerebral malaria. Blocking EphA2 protects against BBB breakdown highlighting EphA2 as a potential therapeutic target for cerebral malaria.

Klíčová slova:

Cerebral malaria – Cytokines – Cytotoxic T cells – Endothelial cells – Mouse models – Parasitic diseases – Plasmodium – T cells


1. Birbeck GL, Molyneux ME, Kaplan PW, Seydel KB, Chimalizeni YF, Kawaza K, et al. Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study. The Lancet Neurology. 2010;9(12):1173–81. doi: 10.1016/S1474-4422(10)70270-2 21056005

2. Brown H, Rogerson S, Taylor T, Tembo M, Mwenechanya J, Molyneux M, et al. Blood-brain barrier function in cerebral malaria in Malawian children. The American journal of tropical medicine and hygiene. 2001;64(3–4):207–13. doi: 10.4269/ajtmh.2001.64.207 11442219

3. Medana IM, Turner GD. Human cerebral malaria and the blood-brain barrier. International journal for parasitology. 2006;36(5):555–68. doi: 10.1016/j.ijpara.2006.02.004 16616145

4. Grab DJ, Chakravorty SJ, van der Heyde H, Stins MF. How can microbial interactions with the blood-brain barrier modulate astroglial and neuronal function? Cellular microbiology. 2011;13(10):1470–8. doi: 10.1111/j.1462-5822.2011.01661.x 21824246

5. Tripathi AK, Sullivan DJ, Stins MF. Plasmodium falciparum-infected erythrocytes decrease the integrity of human blood-brain barrier endothelial cell monolayers. The Journal of infectious diseases. 2007;195(7):942–50. doi: 10.1086/512083 17330783

6. Turner L, Lavstsen T, Berger SS, Wang CW, Petersen JE, Avril M, et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature. 2013;498(7455):502–5. doi: 10.1038/nature12216 23739325

7. Chakravorty SJ, Craig A. The role of ICAM-1 in Plasmodium falciparum cytoadherence. European journal of cell biology. 2005;84(1):15–27. doi: 10.1016/j.ejcb.2004.09.002 15724813

8. Li J, Chang WL, Sun G, Chen HL, Specian RD, Berney SM, et al. Intercellular adhesion molecule 1 is important for the development of severe experimental malaria but is not required for leukocyte adhesion in the brain. Journal of investigative medicine: the official publication of the American Federation for Clinical Research. 2003;51(3):128–40.

9. Amani V, Vigario AM, Belnoue E, Marussig M, Fonseca L, Mazier D, et al. Involvement of IFN-gamma receptor-medicated signaling in pathology and anti-malarial immunity induced by Plasmodium berghei infection. European journal of immunology. 2000;30(6):1646–55. doi: 10.1002/1521-4141(200006)30:6<1646::AID-IMMU1646>3.0.CO;2-0 10898501

10. 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. The Journal of experimental medicine. 2002;195(10):1371–7. doi: 10.1084/jem.20020128 12021316

11. 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. doi: 10.1017/S0031182009991715 20028608

12. Riley EM, Couper KN, Helmby H, Hafalla JC, de Souza JB, Langhorne J, et al. Neuropathogenesis of human and murine malaria. Trends in parasitology. 2010;26(6):277–8. doi: 10.1016/j.pt.2010.03.002 20338809

13. Haque A, Best SE, Unosson K, Amante FH, de Labastida F, Anstey NM, et al. Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria. Journal of immunology (Baltimore, Md: 1950). 2011;186(11):6148–56.

14. Huggins MA, Johnson HL, Jin F, A NS, Hanson LM, LaFrance SJ, et al. Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria. Infection and immunity. 2017;85(5).

15. Shaw TN, Stewart-Hutchinson PJ, Strangward P, Dandamudi DB, Coles JA, Villegas-Mendez A, et al. Perivascular Arrest of CD8+ T Cells Is a Signature of Experimental Cerebral Malaria. PLoS pathogens. 2015;11(11):e1005210. doi: 10.1371/journal.ppat.1005210 26562533

16. Villegas-Mendez A, Greig R, Shaw TN, de Souza JB, Gwyer Findlay E, Stumhofer JS, et al. IFN-gamma-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain. Journal of immunology (Baltimore, Md: 1950). 2012;189(2):968–79.

17. Nacer A, Movila A, Baer K, Mikolajczak SA, Kappe SH, Frevert U. Neuroimmunological blood brain barrier opening in experimental cerebral malaria. PLoS pathogens. 2012;8(10):e1002982. doi: 10.1371/journal.ppat.1002982 23133375

18. Lampugnani MG, Corada M, Andriopoulou P, Esser S, Risau W, Dejana E. Cell confluence regulates tyrosine phosphorylation of adherens junction components in endothelial cells. Journal of cell science. 1997;110 (Pt 17):2065–77.

19. de Lavallade H, Khoder A, Hart M, Sarvaria A, Sekine T, Alsuliman A, et al. Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling. Blood. 2013;122(2):227–38. doi: 10.1182/blood-2012-11-465039 23719297

20. Yamaguchi Y, Pasquale EB. Eph receptors in the adult brain. Current opinion in neurobiology. 2004;14(3):288–96. doi: 10.1016/j.conb.2004.04.003 15194108

21. Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour. Nature reviews Molecular cell biology. 2005;6(6):462–75. doi: 10.1038/nrm1662 15928710

22. Lisabeth EM, Falivelli G, Pasquale EB. Eph receptor signaling and ephrins. Cold Spring Harbor perspectives in biology. 2013;5(9).

23. Hjorthaug HS, Aasheim HC. Ephrin-A1 stimulates migration of CD8+CCR7+ T lymphocytes. European journal of immunology. 2007;37(8):2326–36. doi: 10.1002/eji.200737111 17634955

24. Sharfe N, Nikolic M, Cimpeon L, Van De Kratts A, Freywald A, Roifman CM. EphA and ephrin-A proteins regulate integrin-mediated T lymphocyte interactions. Molecular immunology. 2008;45(5):1208–20. doi: 10.1016/j.molimm.2007.09.019 17980912

25. Fang WB, Ireton RC, Zhuang G, Takahashi T, Reynolds A, Chen J. Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. Journal of cell science. 2008;121(Pt 3):358–68. doi: 10.1242/jcs.017145 18198190

26. Zhou N, Zhao WD, Liu DX, Liang Y, Fang WG, Li B, et al. Inactivation of EphA2 promotes tight junction formation and impairs angiogenesis in brain endothelial cells. Microvascular research. 2011;82(2):113–21. doi: 10.1016/j.mvr.2011.06.005 21726568

27. Togbe D, de Sousa PL, Fauconnier M, Boissay V, Fick L, Scheu S, et al. Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. PLoS ONE. 2008;3(7):e2608. doi: 10.1371/journal.pone.0002608 18612394

28. Howland SW, Poh CM, Gun SY, Claser C, Malleret B, Shastri N, et al. Brain microvessel cross-presentation is a hallmark of experimental cerebral malaria. EMBO molecular medicine. 2013;5(7):984–99. doi: 10.1002/emmm.201202273 23681698

29. Poh CM, Howland SW, Grotenbreg GM, Renia L. Damage to the blood-brain barrier during experimental cerebral malaria results from synergistic effects of CD8+ T cells with different specificities. Infection and immunity. 2014;82(11):4854–64. doi: 10.1128/IAI.02180-14 25156726

30. Swanson PA 2nd, Hart GT, Russo MV, Nayak D, Yazew T, Pena M, et al. CD8+ T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature. PLoS pathogens. 2016;12(12):e1006022. doi: 10.1371/journal.ppat.1006022 27907215

31. Funk SD, Yurdagul A Jr., Albert P, Traylor JG Jr., Jin L, Chen J, et al. EphA2 activation promotes the endothelial cell inflammatory response: a potential role in atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. 2012;32(3):686–95. doi: 10.1161/ATVBAHA.111.242792 22247258

32. Mukai M, Suruga N, Saeki N, Ogawa K. EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/maturation and promote cell adhesion and protrusion formation in HL60 monocytes. BMC cell biology. 2017;18(1):28. doi: 10.1186/s12860-017-0144-x 28851287

33. Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, et al. ADAM12-cleaved ephrin-A1 contributes to lung metastasis. Oncogene. 2014;33(17):2179–90. doi: 10.1038/onc.2013.180 23686306

34. Janes PW, Wimmer-Kleikamp SH, Frangakis AS, Treble K, Griesshaber B, Sabet O, et al. Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10. PLoS biology. 2009;7(10):e1000215. doi: 10.1371/journal.pbio.1000215 19823572

35. Solanas G, Cortina C, Sevillano M, Batlle E. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nature cell biology. 2011;13(9):1100–7. doi: 10.1038/ncb2298 21804545

36. Salaita K, Nair PM, Petit RS, Neve RM, Das D, Gray JW, et al. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science (New York, NY). 2010;327(5971):1380–5.

37. Coulthard MG, Morgan M, Woodruff TM, Arumugam TV, Taylor SM, Carpenter TC, et al. Eph/Ephrin Signaling in Injury and Inflammation. The American Journal of Pathology. 2012;181(5):1493–503. doi: 10.1016/j.ajpath.2012.06.043 23021982

38. Van den Steen PE, Van Aelst I, Starckx S, Maskos K, Opdenakker G, Pagenstecher A. Matrix metalloproteinases, tissue inhibitors of MMPs and TACE in experimental cerebral malaria. Lab Invest. 2006;86(9):873–88. doi: 10.1038/labinvest.3700454 16865090

39. Davis S, Gale NW, Aldrich TH, Maisonpierre PC, Lhotak V, Pawson T, et al. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science (New York, NY). 1994;266(5186):816–9.

40. Himanen JP, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, Nikolov DB. Crystal structure of an Eph receptor-ephrin complex. Nature. 2001;414(6866):933–8. doi: 10.1038/414933a 11780069

41. Wykosky J, Palma E, Gibo DM, Ringler S, Turner CP, Debinski W. Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. Oncogene. 2008;27(58):7260–73. doi: 10.1038/onc.2008.328 18794797

42. Himanen JP, Goldgur Y, Miao H, Myshkin E, Guo H, Buck M, et al. Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex. EMBO reports. 2009;10(7):722–8. doi: 10.1038/embor.2009.91 19525919

43. Ferluga S, Hantgan R, Goldgur Y, Himanen JP, Nikolov DB, Debinski W. Biological and structural characterization of glycosylation on ephrin-A1, a preferred ligand for EphA2 receptor tyrosine kinase. The Journal of biological chemistry. 2013;288(25):18448–57. doi: 10.1074/jbc.M113.464008 23661698

44. Himanen JP, Yermekbayeva L, Janes PW, Walker JR, Xu K, Atapattu L, et al. Architecture of Eph receptor clusters. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(24):10860–5. doi: 10.1073/pnas.1004148107 20505120

45. Holzman LB, Marks RM, Dixit VM. A novel immediate-early response gene of endothelium is induced by cytokines and encodes a secreted protein. Molecular and cellular biology. 1990;10(11):5830–8. doi: 10.1128/mcb.10.11.5830 2233719

46. Cheng N, Chen J. Tumor necrosis factor-alpha induction of endothelial ephrin A1 expression is mediated by a p38 MAPK- and SAPK/JNK-dependent but nuclear factor-kappa B-independent mechanism. The Journal of biological chemistry. 2001;276(17):13771–7. doi: 10.1074/jbc.M009147200 11278471

47. Pandey A, Shao H, Marks RM, Polverini PJ, Dixit VM. Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis. Science (New York, NY). 1995;268(5210):567–9.

48. Vandermosten L, Pham TT, Possemiers H, Knoops S, Van Herck E, Deckers J, et al. Experimental malaria-associated acute respiratory distress syndrome is dependent on the parasite-host combination and coincides with normocyte invasion. Malaria journal. 2018;17(1):102. doi: 10.1186/s12936-018-2251-3 29506544

49. Coulthard MG, Morgan M, Woodruff TM, Arumugam TV, Taylor SM, Carpenter TC, et al. Eph/Ephrin signaling in injury and inflammation. The American journal of pathology. 2012;181(5):1493–503. doi: 10.1016/j.ajpath.2012.06.043 23021982

50. Van den Steen PE, Van Aelst I, Starckx S, Maskos K, Opdenakker G, Pagenstecher A. Matrix metalloproteinases, tissue inhibitors of MMPs and TACE in experimental cerebral malaria. Laboratory investigation; a journal of technical methods and pathology. 2006;86(9):873–88. doi: 10.1038/labinvest.3700454 16865090

51. 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 immunology. 2008;30(10):544–53. doi: 10.1111/j.1365-3024.2008.01053.x 18665903

52. Tripathi AK, Sha W, Shulaev V, Stins MF, Sullivan DJ. Plasmodium falciparum–infected erythrocytes induce NF-κB regulated inflammatory pathways in human cerebral endothelium. Blood. 2009;114(19):4243–52. doi: 10.1182/blood-2009-06-226415 19713460

53. Harris DP, Bandyopadhyay S, Maxwell TJ, Willard B, DiCorleto PE. Tumor necrosis factor (TNF)-alpha induction of CXCL10 in endothelial cells requires protein arginine methyltransferase 5 (PRMT5)-mediated nuclear factor (NF)-kappaB p65 methylation. The Journal of biological chemistry. 2014;289(22):15328–39. doi: 10.1074/jbc.M114.547349 24753255

54. Sorensen EW, Lian J, Ozga AJ, Miyabe Y, Ji SW, Bromley SK, et al. CXCL10 stabilizes T cell-brain endothelial cell adhesion leading to the induction of cerebral malaria. JCI insight. 2018;3(8).

55. Chui R, Dorovini-Zis K. Regulation of CCL2 and CCL3 expression in human brain endothelial cells by cytokines and lipopolysaccharide. Journal of neuroinflammation. 2010;7:1. doi: 10.1186/1742-2094-7-1 20047691

56. Subileau EA, Rezaie P, Davies HA, Colyer FM, Greenwood J, Male DK, et al. Expression of chemokines and their receptors by human brain endothelium: implications for multiple sclerosis. Journal of neuropathology and experimental neurology. 2009;68(3):227–40. doi: 10.1097/NEN.0b013e318197eca7 19225413

57. Chan B, Sukhatme VP. Receptor tyrosine kinase EphA2 mediates thrombin-induced upregulation of ICAM-1 in endothelial cells in vitro. Thrombosis research. 2009;123(5):745–52. doi: 10.1016/j.thromres.2008.07.010 18768213

58. Hess AR, Seftor EA, Gruman LM, Kinch MS, Seftor RE, Hendrix MJ. VE-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway: implications for vasculogenic mimicry. Cancer biology & therapy. 2006;5(2):228–33.

59. Thundyil J, Manzanero S, Pavlovski D, Cully TR, Lok KZ, Widiapradja A, et al. Evidence that the EphA2 receptor exacerbates ischemic brain injury. PLoS ONE. 2013;8(1):e53528. doi: 10.1371/journal.pone.0053528 23308246

60. Hadzijusufovic E, Albrecht-Schgoer K, Huber K, Hoermann G, Grebien F, Eisenwort G, et al. Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site. Leukemia. 2017;31(11):2388–97. doi: 10.1038/leu.2017.245 28757617

61. Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Scientific reports. 2014;4:4874. doi: 10.1038/srep04874 24786396

62. Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson's disease models. Human molecular genetics. 2013;22(16):3315–28. doi: 10.1093/hmg/ddt192 23666528

63. Noberini R, Koolpe M, Peddibhotla S, Dahl R, Su Y, Cosford ND, et al. Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. The Journal of biological chemistry. 2008;283(43):29461–72. doi: 10.1074/jbc.M804103200 18728010

64. Barquilla A, Pasquale EB. Eph receptors and ephrins: therapeutic opportunities. Annual review of pharmacology and toxicology. 2015;55:465–87. doi: 10.1146/annurev-pharmtox-011112-140226 25292427

65. Amato KR, Wang S, Hastings AK, Youngblood VM, Santapuram PR, Chen H, et al. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. The Journal of clinical investigation. 2014;124(5):2037–49. doi: 10.1172/JCI72522 24713656

66. Mimche PN, Brady LM, Bray CF, Lee CM, Thapa M, King TP, et al. The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice. Hepatology (Baltimore, Md). 2015;62(3):900–14.

67. Strangward P, Haley MJ, Shaw TN, Schwartz JM, Greig R, Mironov A, et al. A quantitative brain map of experimental cerebral malaria pathology. PLoS pathogens. 2017;13(3):e1006267. doi: 10.1371/journal.ppat.1006267 28273147

68. Zantek ND, Azimi M, Fedor-Chaiken M, Wang B, Brackenbury R, Kinch MS. E-cadherin regulates the function of the EphA2 receptor tyrosine kinase. Cell growth & differentiation: the molecular biology journal of the American Association for Cancer Research. 1999;10(9):629–38.

69. Tanaka M, Kamata R, Sakai R. EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. The Journal of biological chemistry. 2005;280(51):42375–82. doi: 10.1074/jbc.M503786200 16236711

70. Perez White BE, Ventrella R, Kaplan N, Cable CJ, Thomas PM, Getsios S. EphA2 proteomics in human keratinocytes reveals a novel association with afadin and epidermal tight junctions. Journal of cell science. 2017;130(1):111–8. doi: 10.1242/jcs.188169 27815408

71. Teichert M, Milde L, Holm A, Stanicek L, Gengenbacher N, Savant S, et al. Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nature communications. 2017;8:16106. doi: 10.1038/ncomms16106 28719590

72. Kale S, Hanai J, Chan B, Karihaloo A, Grotendorst G, Cantley L, et al. Microarray analysis of in vitro pericyte differentiation reveals an angiogenic program of gene expression. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2005;19(2):270–1.

73. Puschmann TB, Turnley AM. Eph receptor tyrosine kinases regulate astrocyte cytoskeletal rearrangement and focal adhesion formation. Journal of neurochemistry. 2010;113(4):881–94. doi: 10.1111/j.1471-4159.2010.06655.x 20202079

74. Li X, Wang Y, Wang Y, Zhen H, Yang H, Fei Z, et al. Expression of EphA2 in human astrocytic tumors: correlation with pathologic grade, proliferation and apoptosis. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine. 2007;28(3):165–72.

75. Medana IM, Hunt NH, Chaudhri G. Tumor necrosis factor-alpha expression in the brain during fatal murine cerebral malaria: evidence for production by microglia and astrocytes. The American journal of pathology. 1997;150(4):1473–86. 9095002

76. Medana IM, Chan-Ling T, Hunt NH. Redistribution and degeneration of retinal astrocytes in experimental murine cerebral malaria: relationship to disruption of the blood-retinal barrier. Glia. 1996;16(1):51–64. doi: 10.1002/(SICI)1098-1136(199601)16:1<51::AID-GLIA6>3.0.CO;2-E 8787773

77. 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. Infection and immunity. 2010;78(9):4033–9. doi: 10.1128/IAI.00079-10 20605973

78. Gordon EB, Hart GT, Tran TM, Waisberg M, Akkaya M, Skinner J, et al. Inhibiting the Mammalian target of rapamycin blocks the development of experimental cerebral malaria. mBio. 2015;6(3):e00725. doi: 10.1128/mBio.00725-15 26037126

79. Prevost N, Woulfe D, Tanaka T, Brass LF. Interactions between Eph kinases and ephrins provide a mechanism to support platelet aggregation once cell-to-cell contact has occurred. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(14):9219–24. doi: 10.1073/pnas.142053899 12084815

80. Grau GE, Mackenzie CD, Carr RA, Redard M, Pizzolato G, Allasia C, et al. Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria. The Journal of infectious diseases. 2003;187(3):461–6. doi: 10.1086/367960 12552430

81. Dorovini-Zis K, Schmidt K, Huynh H, Fu W, Whitten RO, Milner D, et al. The neuropathology of fatal cerebral malaria in malawian children. The American journal of pathology. 2011;178(5):2146–58. doi: 10.1016/j.ajpath.2011.01.016 21514429

82. 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. The American journal of tropical medicine and hygiene. 1994;51(5):642–7. 7985757

83. Hochman SE, Madaline TF, Wassmer SC, Mbale E, Choi N, Seydel KB, et al. Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection. mBio. 2015;6(5):e01390–15. doi: 10.1128/mBio.01390-15 26396242

84. Barrera V, Haley MJ, Strangward P, Attree E, Kamiza S, Seydel KB, et al. Comparison of CD8(+) T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria. Frontiers in immunology. 2019;10:1747. doi: 10.3389/fimmu.2019.01747 31396236

85. Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T, et al. Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clinical chemistry. 2004;50(3):490–9. doi: 10.1373/clinchem.2003.026849 14726470

86. Kaushansky A, Douglass AN, Arang N, Vigdorovich V, Dambrauskas N, Kain HS, et al. Malaria parasites target the hepatocyte receptor EphA2 for successful host infection. Science (New York, NY). 2015;350(6264):1089–92.

87. Langlois AC, Marinach C, Manzoni G, Silvie O. Plasmodium sporozoites can invade hepatocytic cells independently of the Ephrin receptor A2. PLoS ONE. 2018;13(7):e0200032. doi: 10.1371/journal.pone.0200032 29975762

88. Noberini R, Lamberto I, Pasquale EB. Targeting Eph receptors with peptides and small molecules: progress and challenges. Seminars in cell & developmental biology. 2012;23(1):51–7.

89. Hahn AS, Kaufmann JK, Wies E, Naschberger E, Panteleev-Ivlev J, Schmidt K, et al. The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma–associated herpesvirus. Nature medicine. 2012;18(6):961–6. doi: 10.1038/nm.2805 22635007

90. Chen J, Sathiyamoorthy K, Zhang X, Schaller S, Perez White BE, Jardetzky TS, et al. Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. Nature microbiology. 2018;3(2):172–80. doi: 10.1038/s41564-017-0081-7 29292384

91. Aaron PA, Jamklang M, Uhrig JP, Gelli A. The blood-brain barrier internalises Cryptococcus neoformans via the EphA2-tyrosine kinase receptor. Cellular microbiology. 2018;20(3).

92. Fonager J, Pasini EM, Braks JA, Klop O, Ramesar J, Remarque EJ, et al. Reduced CD36-dependent tissue sequestration of Plasmodium-infected erythrocytes is detrimental to malaria parasite growth in vivo. The Journal of experimental medicine. 2012;209(1):93–107. doi: 10.1084/jem.20110762 22184632

93. Au—Ruck T, Au—Bittner S, Au—Epping L, Au—Herrmann AM, Au—Meuth SG. Isolation of Primary Murine Brain Microvascular Endothelial Cells. JoVE. 2014(93):e52204. doi: 10.3791/52204 25489873

94. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic acids research. 2001;29(9):e45. doi: 10.1093/nar/29.9.e45 11328886

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