title: A new hypothesis on the manifestation of cerebral malaria: the secret is in the liver.
abstract: Despite the abundance of information on cerebral malaria (CM), the pathogenesis of this disease is not completely understood. At present, two nonexclusive dominant hypotheses exist to explain how the neurological syndrome manifests: the sequestration (or mechanical) hypothesis and the inflammatory hypothesis. The sequestration hypothesis states that sequestration of Plasmodium falciparum-parasitized red blood cells (pRBCs) to brain capillary endothelia causes obstruction of capillary blood flow followed by brain tissue anoxia and coma. The inflammatory hypothesis postulates that P. falciparum infection releases toxic molecules in the circulation, inducing an imbalanced systemic inflammatory response that leads to coagulopathy, brain endothelial cell dysfunction, accumulation of leukocytes in the brain microcirculation, blood brain barrier (BBB) leakage, cerebral vasoconstriction, edema, and coma. However, both hypotheses, even when considered together, are not sufficient to fully explain the pathogenesis of CM. Here, we propose that the development of acute liver failure (ALF) together with BBB breakdown are the necessary and sufficient conditions for the genesis of CM. ALF is characterized by coagulopathy and hepatic encephalopathy (HE) in a patient without pre-existing liver disease. Signs of hepatic dysfunction have been shown to occur in 2.5-40% of CM patients. In addition, recent studies with murine models demonstrated that mice presenting experimental cerebral malaria (ECM) had hepatic damage and brain metabolic changes characteristic of HE. However, the occurrence of CM in patients with mild or without apparent hepatocellular liver damage and the presence of liver damage in non-CM murine models indicate that the development of ALF during malaria infection is not the single factor responsible for neuropathology. To solve this problem, we also propose that BBB breakdown contributes to the pathogenesis of CM and synergizes with hepatic failure to cause neurological signs and symptoms. BBB dysfunction would thus occur in CM by a mechanism similar to the one occurring in sepsis and is in agreement with the inflammatory hypothesis. Nevertheless, differently from in the inflammatory hypothesis, BBB leakage would facilitate the penetration of ammonia and other toxins into the brain parenchyma, but would not be sufficient to cause CM when occurring alone. We believe our hypothesis better explains the pathogenesis of CM, does not have problems to deal with the exception data not explained by the previous hypotheses, and reveals new targets for adjunctive therapy.
authors: Laboratório de Pesquisas em Malária, Instituto Oswaldo Cruz and Centro de Pesquisa Diagnóstico e Treinamento em Malária, Fiocruz, Rio de Janeiro, RJ, Brazil; Department of Pathology, Albert Einstein College of Medicine, The Bronx, NY, USA. Electronic address: yuri.chaves@einstein.yu.edu.
authors: Yuri Chaves
authors: YC
authors: Martins
authors: Cláudio Tadeu
authors: CT
authors: Daniel-Ribeiro
mesh_terms: D001812:Blood-Brain Barrier / Q000473:pathology*; D004912:Erythrocytes / Q000469:parasitology*; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000473:pathology; D006801:Humans; D017114:Liver Failure, Acute / Q000150:complications*; D016779:Malaria, Cerebral / Q000209:etiology* / Q000469:parasitology; D008954:Models, Biological; D010963:Plasmodium falciparum
references: Ann Trop Paediatr. 2011;31(4):351-6
references: 22041470
references: J Immunol. 2010 Aug 15;185(4):2482-92
references: 20631310
references: Biol Cell. 1992;74(2):161-78
references: 1596638
references: Parasitol Today. 1994 Oct;10(10):412-4
references: 15275553
references: Trans R Soc Trop Med Hyg. 2003 Mar-Apr;97(2):236-41
references: 14584384
references: Clin Infect Dis. 1994 Sep;19(3):480-5
references: 7811867
references: Pharmacol Ther. 2003 Aug;99(2):221-60
references: 12888113
references: Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):E1772-81
references: 22619330
references: Trends Parasitol. 2010 Jan;26(1):11-5
references: 19932638
references: Pediatrics. 2008 Jul;122(1):e92-9
references: 18541616
references: Parasit Vectors. 2012 Jul 30;5:154
references: 22846165
references: Malar J. 2013 Apr 24;12:138
references: 23617605
references: Afr Health Sci. 2012 Jun;12(2):90-7
references: 23056012
references: Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):1035-40
references: 23277579
references: Eur J Med Chem. 2011 May;46(5):1757-67
references: 21396743
references: Clin Infect Dis. 1995 Sep;21(3):577-87
references: 8527547
references: Mol Biol Cell. 2000 Dec;11(12):4131-42
references: 11102513
references: Mediterr J Hematol Infect Dis. 2012;4(1):e2012061
references: 23170190
references: Crit Care Med. 2009 Feb;37(2):516-22
references: 19114891
references: Malar J. 2011 Sep 17;10:267
references: 21923924
references: Int J Parasitol. 2006 May 1;36(5):569-82
references: 16678181
references: Lancet Neurol. 2005 Dec;4(12):827-40
references: 16297841
references: Indian Pediatr. 2007 Jun;44(6):433-4
references: 17620697
references: Microbes Infect. 2002 Mar;4(3):291-300
references: 11909739
references: Biotherapy. 1994;7(3-4):211-21
references: 7865352
references: Int Immunol. 2004 Jun;16(6):787-98
references: 15096477
references: Front Immunol. 2012 Apr 25;3:85
references: 22566965
references: Trends Neurosci. 2001 Dec;24(12):719-25
references: 11718877
references: J Immunol. 2003 Feb 15;170(4):2221-8
references: 12574396
references: PLoS Med. 2008 Jun 17;5(6):e136
references: 18563965
references: Mol Biochem Parasitol. 2009 Aug;166(2):99-108
references: 19450727
references: Expert Rev Anti Infect Ther. 2011 Sep;9(9):803-19
references: 21905788
references: Trop Med Int Health. 2006 Jun;11(6):817-23
references: 16772003
references: Metab Brain Dis. 2013 Jun;28(2):155-9
references: 23479402
references: Neurochem Int. 2004 Mar;44(4):185-98
references: 14602081
references: PLoS One. 2011 Mar 03;6(3):e14741
references: 21390226
references: J Neuroimmune Pharmacol. 2012 Jun;7(2):477-87
references: 22391863
references: Southeast Asian J Trop Med Public Health. 2005 Nov;36(6):1359-70
references: 16610635
references: Mol Biochem Parasitol. 2004 Sep;137(1):55-64
references: 15279951
references: J Immunol. 2002 Sep 1;169(5):2323-9
references: 12193697
references: PLoS One. 2008 Aug 22;3(8):e3037
references: 18725947
references: Microbes Infect. 2006 Jul;8(8):2305-16
references: 16829152
references: Rev Neurol (Paris). 2012 Mar;168(3):239-56
references: 22386676
references: Am J Pathol. 2001 Sep;159(3):1105-12
references: 11549603
references: PLoS One. 2012;7(2):e32048
references: 22348145
references: Neurochem Int. 2012 Jun;60(7):662-71
references: 22067133
references: J Biol Chem. 2012 Aug 3;287(32):26630-46
references: 22696214
references: J Gastroenterol Hepatol. 2005 Sep;20(9):1322-32
references: 16105116
references: Int J Exp Pathol. 2009 Apr;90(2):119-30
references: 19335550
references: Trans R Soc Trop Med Hyg. 2004 Dec;98(12):753-4
references: 15485707
references: Trends Parasitol. 2009 Jul;25(7):314-8
references: 19541540
references: Trends Parasitol. 2010 Jun;26(6):271-2
references: 20335068
references: Clin Infect Dis. 2011 Aug;53(4):349-55
references: 21810747
references: Life Sci. 2012 Oct 15;91(13-14):687-92
references: 22820174
references: Am J Trop Med Hyg. 2010 Nov;83(5):981-9
references: 21036824
references: Semin Thromb Hemost. 2010 Jun;36(4):437-43
references: 20614395
references: Trans R Soc Trop Med Hyg. 2000 Apr;94 Suppl 1:S1-90
references: 11103309
references: J Infect Dis. 1996 May;173(5):1281-4
references: 8627087
references: Parasitology. 2005;130 Suppl:S45-62
references: 16281992
references: Trop Med Parasitol. 1994 Dec;45(4):298-302
references: 7716391
references: Am J Trop Med Hyg. 2002 Feb;66(2):140-2
references: 12135283
references: J Proteome Res. 2012 Oct 5;11(10):4992-5004
references: 22838963
references: Parasitol Today. 1994 Oct;10(10):410-2
references: 15275552
references: Int J Parasitol. 2006 May 1;36(5):555-68
references: 16616145
references: PLoS Pathog. 2012 Feb;8(2):e1002504
references: 22319445
references: J Infect Dis. 1996 Nov;174(5):1091-7
references: 8896514
references: Hum Mol Genet. 2008 Jul 15;17(14):2190-5
references: 18413324
references: Int J Parasitol. 2012 Nov;42(12):1099-105
references: 23022617
references: Nat Med. 2006 Dec;12(12):1417-22
references: 17099710
references: Nat Med. 2007 Jun;13(6):703-10
references: 17496899
references: Pediatrics. 2007 Feb;119(2):e360-6
references: 17224457
references: Exp Biol Med (Maywood). 2006 Jun;231(6):1176-81
references: 16741072
references: Clin Infect Dis. 2012 Apr;54(8):1080-90
references: 22412067
references: J Immunol. 2001 Nov 15;167(10):5928-34
references: 11698470
references: Acta Trop. 2011 Oct-Nov;120(1-2):31-9
references: 21722620
references: Infect Immun. 2011 May;79(5):1882-8
references: 21343349
references: J Neurosci. 2005 Aug 10;25(32):7352-8
references: 16093385
references: Expert Rev Anti Infect Ther. 2013 Feb;11(2):211-21
references: 23409826
references: Best Pract Res Clin Gastroenterol. 2012 Feb;26(1):3-16
references: 22482521
references: J Immunol. 2011 Sep 15;187(6):2885-97
references: 21880980
references: Thromb Haemost. 2005 Aug;94(2):336-40
references: 16113823
references: Exp Parasitol. 2006 Aug;113(4):256-61
references: 16540109
references: J Mol Med (Berl). 2008 Oct;86(10):1097-111
references: 18641963
references: Trends Parasitol. 2002 Aug;18(8):360-6
references: 12377286
references: Nat Rev Immunol. 2006 Dec;6(12):895-906
references: 17110955
references: Am J Pathol. 2010 Mar;176(3):1306-15
references: 20110412
references: Appl Neuropsychol. 1997;4(4):238-43
references: 16318473
references: Am J Trop Med Hyg. 2001 Dec;65(6):828-33
references: 11791981
references: J Infect Dis. 2010 Aug 15;202(4):638-47
references: 20617923
references: Eur J Immunol. 2004 Apr;34(4):972-80
references: 15048707
references: Parasitol Today. 2000 Jun;16(6):228-32
references: 10827427
references: Am J Pathol. 2001 Jan;158(1):163-72
references: 11141489
references: Cochrane Database Syst Rev. 2000;(2):CD000972
references: 10796562
references: Trends Parasitol. 2006 Nov;22(11):503-8
references: 16979941
references: J Cell Biol. 2003 May 12;161(3):653-60
references: 12743111
references: Neuroimmunomodulation. 2009;16(2):134-45
references: 19212133
references: Neurochem Int. 2012 Jun;60(7):690-6
references: 22382077
references: J Biol Chem. 2007 May 11;282(19):14505-14
references: 17369263
references: Hum Pathol. 2011 Sep;42(9):1230-9
references: 21396681
references: PLoS Negl Trop Dis. 2013 Apr 04;7(4):e2155
references: 23593522
references: J Immunol. 2012 Feb 15;188(4):1905-14
references: 22238458