Breaking down the blood-brain barrier: signaling a path to cerebral malaria?

Cerebral malaria is a major killer in the developing world, but we still know very little about the causes of this disease. How does Plasmodium falciparum cause such a devastating neurological disease while it is in the brain vasculature? Why do some patients die, whereas others survive? What processes contribute to disease in the brain, and can we reverse them? Here, the latest evidence from post-mortem, in vitro and animal studies is reviewed to highlight the role of blood-brain barrier breakdown in cerebral malaria. Blood-brain barrier integrity is disturbed during severe malaria, causing leakage of cerebral vessels. Understanding how this happens and how it contributes to the pathogenesis of coma may provide new opportunities for the treatment of cerebral malaria.

[1]  D Lee,et al.  The World Health Organisation , 2001, British journal of perioperative nursing : the journal of the National Association of Theatre Nurses.

[2]  B. M. Greenwood,et al.  TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria , 1990, The Lancet.

[3]  Kevin Marsh,et al.  Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria , 1998, Nature Medicine.

[4]  C. Newbold,et al.  Differential Binding of Clonal Variants of Plasmodium falciparum to Allelic Forms of Intracellular Adhesion Molecule 1 Determined by Flow Adhesion Assay , 2000, Infection and Immunity.

[5]  C. Whitty,et al.  A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. , 1999, The American journal of pathology.

[6]  R. Rothlein,et al.  Intercellular adhesion molecule-1 (ICAM-1) expression and cell signaling cascades. , 2000, Free radical biology & medicine.

[7]  N. Day,et al.  Reactive nitrogen intermediates and outcome in severe adult malaria. , 1998, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[8]  M. Aikawa,et al.  Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. , 1991, The American journal of tropical medicine and hygiene.

[9]  L. Rubin,et al.  Signal transduction at the blood-brain barrier. , 1995, Biochemical Society transactions.

[10]  Joseph D. Smith,et al.  Correction for Smith et al., Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: A parasite adhesion trait implicated in cerebral malaria , 2000, Proceedings of the National Academy of Sciences.

[11]  J. Turner.  'Putting the squeeze' on the tight junction: understanding cytoskeletal regulation. , 2000, Seminars in cell & developmental biology.

[12]  T. Chan-Ling,et al.  Central nervous system in cerebral malaria: ‘Innocent bystander’ or active participant in the induction of immunopathology? , 2001, Immunology and cell biology.

[13]  V. Perry,et al.  The blood-brain barrier and the inflammatory response. , 1997, Molecular medicine today.

[14]  B. Maegraith.  Pathological Processes in Malaria and Blackwater Fever , 1949, The Indian Medical Gazette.

[15]  I. Clark,et al.  Breakdown of the blood-brain barrier in murine cerebral malaria , 1988, Parasitology.

[16]  N. White,et al.  Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. , 1985, The American journal of pathology.

[17]  T. Chan-Ling,et al.  Redistribution and degeneration of retinal astrocytes in experimental murine cerebral malaria: Relationship to disruption of the blood‐retinal barrier , 1996, Glia.

[18]  R. Snow,et al.  The past, present and future of childhood malaria mortality in Africa. , 2001, Trends in parasitology.

[19]  M. Fried,et al.  Maternal malaria and parasite adhesion , 1998, Journal of Molecular Medicine.

[20]  J. Romijn,et al.  Nitric oxides in plasma, urine, and cerebrospinal fluid in patients with severe falciparum malaria. , 1998, The American journal of tropical medicine and hygiene.

[21]  T. Taylor,et al.  Blood-brain barrier function in cerebral malaria in Malawian children. , 2001, The American journal of tropical medicine and hygiene.

[22]  M. Madigan,et al.  Correlation between enhanced vascular permeability, up-regulation of cellular adhesion molecules and monocyte adhesion to the endothelium in the retina during the development of fatal murine cerebral malaria. , 1996, The American journal of pathology.

[23]  Davis,et al.  An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration. , 1994, The American journal of pathology.

[24]  L. Rubin,et al.  Cell adhesion, cell junctions and the blood—brain barrier , 1996, Current Opinion in Neurobiology.

[25]  I. Clark,et al.  The biological basis of malarial disease. , 1997, International journal for parasitology.

[26]  D. Kwiatkowski,et al.  Neurological sequelae of cerebral malaria in children , 1990, The Lancet.

[27]  H. Chapel,et al.  Function of the blood-cerebrospinal fluid barrier in human cerebral malaria: rejection of the permeability hypothesis. , 1986, The American journal of tropical medicine and hygiene.

[28]  Ching Li,et al.  Rodent malarias: the mouse as a model for understanding immune responses and pathology induced by the erythrocytic stages of the parasite , 2001, Medical Microbiology and Immunology.

[29]  N. Day,et al.  Cellular stress and injury responses in the brains of adult Vietnamese patients with fatal Plasmodium falciparum malaria , 2001, Neuropathology and applied neurobiology.

[30]  A. Craig,et al.  Molecular mechanisms of sequestration in malaria , 1994, Parasitology.

[31]  R. Egleton,et al.  Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier , 2001, Trends in Neurosciences.

[32]  A. Craig,et al.  Molecules on the surface of the Plasmodium falciparum infected erythrocyte and their role in malaria pathogenesis and immune evasion. , 2001, Molecular and biochemical parasitology.

[33]  B. Kendall,et al.  Brain swelling and ischaemia in Kenyans with cerebral malaria. , 1994, Archives of disease in childhood.

[34]  B. Greenwood.  Malaria mortality and morbidity in Africa. , 1999, Bulletin of the World Health Organization.

[35]  W. Mayhan.  Regulation of Blood—Brain Barrier Permeability , 2001, Microcirculation.

[36]  J. Reeder,et al.  Parasite adhesion and immune evasion in placental malaria. , 2001, Trends in parasitology.

[37]  N. Hunt,et al.  Pathology of fatal and resolving Plasmodium berghei cerebral malaria in mice , 1992, Parasitology.

[38]  D. Granger,et al.  Assessing Vascular Permeability during Experimental Cerebral Malaria by a Radiolabeled Monoclonal Antibody Technique , 2001, Infection and Immunity.

[39]  S. Fox,et al.  Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity. , 1998, The American journal of pathology.

[40]  R. Hunter,et al.  Cytokine profile suggesting that murine cerebral malaria is an encephalitis , 1997, Infection and immunity.

[41]  T. Taylor,et al.  Cytokine expression in the brain in human cerebral malaria. , 1999, The Journal of infectious diseases.

[42]  A. Strosberg,et al.  Intercellular adhesion molecule 1 activation induces tyrosine phosphorylation of the cytoskeleton-associated protein cortactin in brain microvessel endothelial cells. , 1994, The Journal of biological chemistry.

[43]  Shoichiro Tsukita,et al.  Multifunctional strands in tight junctions , 2001, Nature Reviews Molecular Cell Biology.

[44]  T. Chan-Ling,et al.  Reactive changes of retinal microglia during fatal murine cerebral malaria: effects of dexamethasone and experimental permeabilization of the blood-brain barrier. , 2000, The American journal of pathology.

[45]  White,et al.  Evidence of blood–brain barrier dysfunction in human cerebral malaria , 1999, Neuropathology and applied neurobiology.

[46]  J. Greenwood,et al.  ICAM-1-Coupled Cytoskeletal Rearrangements and Transendothelial Lymphocyte Migration Involve Intracellular Calcium Signaling in Brain Endothelial Cell Lines1 , 2000, The Journal of Immunology.

[47]  M. Aikawa.  Human cerebral malaria. , 1988, The American journal of tropical medicine and hygiene.

[48]  F. Gay-andrieu,et al.  Ultrastructural aspects of Plasmodium falciparum-infected erythrocyte adherence to endothelial cells of Saimiri brain microvasculature. , 1996, The American journal of tropical medicine and hygiene.

[49]  L. Rubin,et al.  The cell biology of the blood-brain barrier. , 1999, Annual review of neuroscience.

[50]  A. Nagafuchi.  Molecular architecture of adherens junctions. , 2001, Current opinion in cell biology.

[51]  S. Tsukita,et al.  Pores in the Wall , 2000, The Journal of cell biology.

[52]  B. Das,et al.  Vascular clogging, mononuclear cell margination, and enhanced vascular permeability in the pathogenesis of human cerebral malaria. , 1994, The American journal of tropical medicine and hygiene.

[53]  W. Hickey.  Basic principles of immunological surveillance of the normal central nervous system , 2001, Glia.

[54]  K. Mendis,et al.  Dynamics of fever and serum levels of tumor necrosis factor are closely associated during clinical paroxysms in Plasmodium vivax malaria. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[55]  L. Sanni.  The role of cerebral oedema in the pathogenesis of cerebral malaria , 2001, Redox report : communications in free radical research.

[56]  A. Strosberg,et al.  ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells. , 1998, Journal of immunology.

[57]  P. Adamson,et al.  Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. , 1999, Journal of immunology.

[58]  R. Udomsangpetch,et al.  Inducible nitric oxide synthase expression is increased in the brain in fatal cerebral malaria , 2000, Histopathology.

[59]  D. Kwiatkowski,et al.  The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. , 1996, The Journal of infectious diseases.

[60]  N. Day,et al.  Blood–brain barrier function in cerebral malaria and CNS infections in Vietnam , 2000, Neurology.

[61]  M. Dietrich,et al.  High Levels of Inducible Nitric Oxide Synthase mRNA Are Associated with Increased Monocyte Counts in Blood and Have a Beneficial Role in Plasmodium falciparum Malaria , 2000, Infection and Immunity.

[62]  W. Eling,et al.  Ultrastructural changes in the blood-brain barrier of mice infected with Plasmodium berghei. , 1992, Acta Leidensia.

[63]  R. Udomsangpetch,et al.  Involvement of cytokines in the histopathology of cerebral malaria. , 1997, The American journal of tropical medicine and hygiene.