211
Views
53
CrossRef citations to date
0
Altmetric
Review

Immunopathogenesis of falciparum malaria: implications for adjunctive therapy in the management of severe and cerebral malaria

, &
Pages 803-819 | Published online: 10 Jan 2014

References

  • WHO. World Health Organization: World Malaria Report. World Health Organization, Geneva, Switzerland (2010).
  • WHO. World Health Organization: Management of Severe Malaria: A Practical Handbook. (2nd Edition). World Health Organization, Geneva, Switzerland (2000).
  • Dondorp AM, Fanello CI, Hendriksen IC et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet376(9753), 1647–1657 (2010).
  • Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet366(9487), 717–725 (2005).
  • John CC, Bangirana P, Byarugaba J et al. Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics122(1), e92–e99 (2008).
  • Idro R, Marsh K, John CC, Newton CR. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr. Res.68(4), 267–274 (2010).
  • Idro R, Kakooza-Mwesige A, Balyejjussa S et al. Severe neurological sequelae and behaviour problems after cerebral malaria in Ugandan children. BMC Res. Notes3, 104 (2010).
  • O’Meara WP, Bejon P, Mwangi TW et al. Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet372(9649), 1555–1562 (2008).
  • Osler W. The Evolution of Modern Medicine; a Series of Lectures Delivered at Yale University on the Silliman Foundation, in April, 1913. Yale University Press, New Haven, CT, USA (1921).
  • Medzhitov R. Damage control in host–pathogen interactions. Proc. Natl Acad. Sci. USA106(37), 15525–15526 (2009).
  • Langhorne J, Ndungu FM, Sponaas AM, Marsh K. Immunity to malaria: more questions than answers. Nat. Immunol.9(7), 725–732 (2008).
  • Doolan DL, Dobano C, Baird JK. Acquired immunity to malaria. Clin. Microbiol. Rev.22(1), 13–36 (2009).
  • Kwiatkowski D, Hill AV, Sambou I et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet336(8725), 1201–1204 (1990).
  • Malaguarnera L, Musumeci S. The immune response to Plasmodium falciparum malaria. Lancet Infect. Dis.2(8), 472–478 (2002).
  • Lyke KE, Burges R, Cissoko Y et al. Serum levels of the proinflammatory cytokines interleukin-1 β (IL-1β), IL-6, IL-8, IL-10, tumor necrosis factor α, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect. Immun.72(10), 5630–5637 (2004).
  • Day NP, Hien TT, Schollaardt T et al. The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. J. Infect. Dis.180(4), 1288–1297 (1999).
  • Rogerson SJ, Tembenu R, Dobano C, Plitt S, Taylor TE, Molyneux ME. Cytoadherence characteristics of Plasmodium falciparum-infected erythrocytes from Malawian children with severe and uncomplicated malaria. Am. J. Trop. Med. Hyg.61(3), 467–472 (1999).
  • Armah H, Dodoo AK, Wiredu EK et al. High-level cerebellar expression of cytokines and adhesion molecules in fatal, paediatric, cerebral malaria. Ann. Trop. Med. Parasitol.99(7), 629–647 (2005).
  • Brown H, Rogerson S, Taylor T et al. Blood–brain barrier function in cerebral malaria in Malawian children. Am. J. Trop. Med. Hyg.64(3–4), 207–213 (2001).
  • Dondorp AM. Clinical significance of sequestration in adults with severe malaria. Transfus. Clin. Biol.15(1–2), 56–57 (2008).
  • Pain A, Ferguson DJ, Kai O et al. Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. Proc. Natl Acad. Sci. USA98(4), 1805–1810 (2001).
  • Taylor TE, Fu WJ, Carr RA et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat. Med.10(2), 143–145 (2004).
  • Pongponratn E, Turner GD, Day NP et al. An ultrastructural study of the brain in fatal Plasmodium falciparum malaria. Am. J. Trop. Med. Hyg.69(4), 345–359 (2003).
  • David PH, Hommel M, Miller LH, Udeinya IJ, Oligino LD. Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes. Proc. Natl Acad. Sci. USA80(16), 5075–5079 (1983).
  • Ochola LB, Siddondo BR, Ocholla H et al. Specific receptor usage in Plasmodium falciparum cytoadherence is associated with disease outcome. PLoS One6(3), e14741 (2011).
  • Newbold C, Warn P, Black G et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am. J. Trop. Med. Hyg.57(4), 389–398 (1997).
  • MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am. J. Pathol.119(3), 385–401 (1985).
  • Turner GD, Morrison H, Jones M 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. Am. J. Pathol.145(5), 1057–1069 (1994).
  • Dorovini-Zis K, Schmidt K, Huynh H et al. The neuropathology of fatal cerebral malaria in malawian children. Am. J. Pathol.178(5), 2146–2158 (2011).
  • Kaul DK, Roth EF Jr, Nagel RL, Howard RJ, Handunnetti SM. Rosetting of Plasmodium falciparum-infected red blood cells with uninfected red blood cells enhances microvascular obstruction under flow conditions. Blood78(3), 812–819 (1991).
  • Rowe A, Obeiro J, Newbold CI, Marsh K. Plasmodium falciparum rosetting is associated with malaria severity in Kenya. Infect. Immun.63(6), 2323–2326 (1995).
  • Carlson J, Helmby H, Hill AV, Brewster D, Greenwood BM, Wahlgren M. Human cerebral malaria: association with erythrocyte rosetting and lack of anti-rosetting antibodies. Lancet336(8729), 1457–1460 (1990).
  • Rowe JA, Moulds JM, Newbold CI, Miller LH. Plasmodium falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature388(6639), 292–295 (1997).
  • Doumbo OK, Thera MA, Kone AK et al. High levels of Plasmodium falciparum rosetting in all clinical forms of severe malaria in African children. Am. J. Trop. Med. Hyg.81(6), 987–993 (2009).
  • Fiedler U, Reiss Y, Scharpfenecker M et al. Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation. Nat. Med.12(2), 235–239 (2006).
  • Larkin D, de Laat B, Jenkins PV et al. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. PLoS Pathog.5(3), e1000349 (2009).
  • Valentijn KM, Sadler JE, Valentijn JA, Voorberg J, Eikenboom J. Functional architecture of Weibel–Palade bodies. Blood117(19), 5033–5043 (2011).
  • Bridges DJ, Bunn J, van Mourik JA et al. Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings. Blood115(7), 1472–1474 (2010).
  • Francischetti IM, Seydel KB, Monteiro RQ. Blood coagulation, inflammation, and malaria. Microcirculation15(2), 81–107 (2008).
  • Moxon CA, Heyderman RS, Wassmer SC. Dysregulation of coagulation in cerebral malaria. Mol. Biochem. Parasitol.166(2), 99–108 (2009).
  • Schofield L, Grau GE. Immunological processes in malaria pathogenesis. Nat. Rev. Immunol.5(9), 722–735 (2005).
  • Gillrie MR, Krishnegowda G, Lee K et al. Src-family kinase dependent disruption of endothelial barrier function by Plasmodium falciparum merozoite proteins. Blood110(9), 3426–3435 (2007).
  • Beare NA, Harding SP, Taylor TE, Lewallen S, Molyneux ME. Perfusion abnormalities in children with cerebral malaria and malarial retinopathy. J. Infect. Dis.199(2), 263–271 (2009).
  • Dondorp AM, Ince C, Charunwatthana P et al. Direct in vivo assessment of microcirculatory dysfunction in severe falciparum malaria. J. Infect. Dis.197(1), 79–84 (2008).
  • Latourette MT, Siebert JE, Barto RJ Jr et al. Magnetic resonance imaging research in Sub-Saharan Africa: challenges and satellite-based networking implementation. J. Digit. Imaging24(4), 729–738 (2010).
  • White NJ, Turner GD, Medana IM, Dondorp AM, Day NP. The murine cerebral malaria phenomenon. Trends Parasitol.26(1), 11–15 (2010).
  • de Souza JB, Hafalla JC, Riley EM, Couper KN. Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease. Parasitology137(5), 755–772 (2010).
  • Riley EM, Couper KN, Helmby H et al. Neuropathogenesis of human and murine malaria. Trends Parasitol.26(6), 277–278 (2010).
  • Stevenson MM, Gros P, Olivier M, Fortin A, Serghides L. Cerebral malaria: human versus mouse studies. Trends Parasitol.26(6), 274–275 (2010).
  • John CC, Kutamba E, Mugarura K, Opoka RO. Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria. Expert Rev. Anti. Infect. Ther.8(9), 997–1008 (2011).
  • Mishra SK, Newton CR. Diagnosis and management of the neurological complications of falciparum malaria. Nat. Rev. Neurol.5(4), 189–198 (2009).
  • Maitland K, Kiguli S, Opoka RO et al. Mortality after fluid bolus in African children with severe infection. N. Engl. J. Med.364(26), 2483–2495 (2011).
  • Myburgh JA. Fluid resuscitation in acute illness–time to reappraise the basics. N. Engl. J. Med.364(26), 2543–2544 (2011).
  • Yudt MR, Cidlowski JA. The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene. Mol. Endocrinol.16(8), 1719–1726 (2002).
  • Schaaf MJ, Cidlowski JA. Molecular mechanisms of glucocorticoid action and resistance. J. Steroid. Biochem. Mol. Biol.83(1–5), 37–48 (2002).
  • Woodruff AW, Dickinson CJ. Use of dexamethasone in cerebral malaria. Br. Med. J.3(5609), 31–32 (1968).
  • Daroff RB, Deller JJ Jr, Kastl AJ Jr, Blocker W Jr. Cerebral malaria. JAMA202(8), 679–682 (1967).
  • Oriscello RG. Cerebral malaria. Br. Med. J.3(5618), 617–618 (1968).
  • Hoffman SL, Rustama D, Punjabi NH et al. High-dose dexamethasone in quinine-treated patients with cerebral malaria: a double-blind, placebo-controlled trial. J. Infect. Dis.158(2), 325–331 (1988).
  • Warrell DA, Looareesuwan S, Warrell MJ et al. Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients. N. Engl. J. Med.306(6), 313–319 (1982).
  • Warrell DA, White NJ, Warrell MJ. Dexamethasone deleterious in cerebral malaria. Br. Med. J. (Clin. Res. Ed.)285(6355), 1652 (1982).
  • Taylor TE, Molyneux ME, Wirima JJ, Borgstein A, Goldring JD, Hommel M. Intravenous immunoglobulin in the treatment of paediatric cerebral malaria. Clin. Exp. Immunol.90(3), 357–362 (1992).
  • Havlik I, Looareesuwan S, Vannaphan S et al. Curdlan sulphate in human severe/cerebral Plasmodium falciparum malaria. Trans. R. Soc. Trop. Med. Hyg.99(5), 333–340 (2005).
  • Hemmer CJ, Kern P, Holst FG, Nawroth PP, Dietrich M. Neither heparin nor acetylsalicylic acid influence the clinical course in human Plasmodium falciparum malaria: a prospective randomized study. Am. J. Trop. Med. Hyg.45(5), 608–612 (1991).
  • Brown H, Turner G, Rogerson S et al. Cytokine expression in the brain in human cerebral malaria. J. Infect. Dis.180(5), 1742–1746 (1999).
  • Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science237(4819), 1210–1212 (1987).
  • van Hensbroek MB, Palmer A, Onyiorah E et al. The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. J. Infect. Dis.174(5), 1091–1097 (1996).
  • Herve P, Flesch M, Tiberghien P et al. Phase I-II trial of a monoclonal anti-tumor necrosis factor α antibody for the treatment of refractory severe acute graft-versus-host disease. Blood79(12), 3362–3368 (1992).
  • Zabel P, Schade FU, Schlaak M. Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology187(3–5), 447–463 (1993).
  • Wenisch C, Looareesuwan S, Wilairatana P et al. Effect of pentoxifylline on cytokine patterns in the therapy of complicated Plasmodium falciparum malaria. Am. J. Trop. Med. Hyg.58(3), 343–347 (1998).
  • Das BK, Mishra S, Padhi PK et al. Pentoxifylline adjunct improves prognosis of human cerebral malaria in adults. Trop. Med. Int. Health8(8), 680–684 (2003).
  • Di Perri G, Di Perri IG, Monteiro GB et al. Pentoxifylline as a supportive agent in the treatment of cerebral malaria in children. J. Infect. Dis.171(5), 1317–1322 (1995).
  • Looareesuwan S, Wilairatana P, Vannaphan S et al. Pentoxifylline as an ancillary treatment for severe falciparum malaria in Thailand. Am. J. Trop. Med. Hyg.58(3), 348–353 (1998).
  • Lell B, Kohler C, Wamola B et al. Pentoxifylline as an adjunct therapy in children with cerebral malaria. Malar. J.9, 368 (2010).
  • Hemmer CJ, Hort G, Chiwakata CB et al. Supportive pentoxifylline in falciparum malaria: no effect on tumor necrosis factor α levels or clinical outcome: a prospective, randomized, placebo-controlled study. Am. J. Trop. Med. Hyg.56(4), 397–403 (1997).
  • de Souza JB, Okomo U, Alexander ND et al. Oral activated charcoal prevents experimental cerebral malaria in mice and in a randomized controlled clinical trial in man did not interfere with the pharmacokinetics of parenteral artesunate. PLoS One5(4), e9867 (2010).
  • Engwerda CR, Mynott TL, Sawhney S, De Souza JB, Bickle QD, Kaye PM. Locally up-regulated lymphotoxin α, not systemic tumor necrosis factor α, is the principle mediator of murine cerebral malaria. J. Exp. Med.195(10), 1371–1377 (2002).
  • Phillips A, Bassett P, Zeki S, Newman S, Pasvol G. Risk factors for severe disease in adults with falciparum malaria. Clin. Infect. Dis.48(7), 871–878 (2009).
  • Marsh K, Forster D, Waruiru C et al. Indicators of life-threatening malaria in African children. N. Engl. J. Med.332(21), 1399–1404 (1995).
  • Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q. J. Med.71(265), 441–459 (1989).
  • Hanson J, Lee SJ, Mohanty S et al. A simple score to predict the outcome of severe malaria in adults. Clin. Infect. Dis.50(5), 679–685 (2010).
  • Helbok R, Kendjo E, Issifou S et al. The Lambarene Organ Dysfunction Score (LODS) is a simple clinical predictor of fatal malaria in African children. J. Infect. Dis.200(12), 1834–1841 (2009).
  • Beare NA, Taylor TE, Harding SP, Lewallen S, Molyneux ME. Malarial retinopathy: a newly established diagnostic sign in severe malaria. Am. J. Trop. Med. Hyg.75(5), 790–797 (2006).
  • White VA, Lewallen S, Beare NA, Molyneux ME, Taylor TE. Retinal pathology of pediatric cerebral malaria in Malawi. PLoS One4(1), e4317 (2009).
  • Buyse M, Sargent DJ, Grothey A, Matheson A, de Gramont A. Biomarkers and surrogate end points – the challenge of statistical validation. Nat. Rev. Clin. Oncol.7(6), 309–317 (2010).
  • Standage SW, Wong HR. Biomarkers for pediatric sepsis and septic shock. Expert Rev. Anti. Infect. Ther.9(1), 71–79 (2011).
  • Marshall JC, Reinhart K. Biomarkers of sepsis. Crit. Care Med.37(7), 2290–2298 (2009).
  • Lee WG, Kim YG, Chung BG, Demirci U, Khademhosseini A. Nano/microfluidics for diagnosis of infectious diseases in developing countries. Adv. Drug. Deliv. Rev.62(4–5), 449–457 (2011).
  • Grau GE, Taylor TE, Molyneux ME et al. Tumor necrosis factor and disease severity in children with falciparum malaria. N. Engl. J. Med.320(24), 1586–1591 (1989).
  • Kern P, Hemmer CJ, Van Damme J, Gruss HJ, Dietrich M. Elevated tumor necrosis factor α and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria. Am. J. Med.87(2), 139–143 (1989).
  • Akanmori BD, Kurtzhals JA, Goka BQ et al. Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria. Eur. Cytokine. Netw.11(1), 113–118 (2000).
  • Tchinda VH, Tadem AD, Tako EA et al. Severe malaria in Cameroonian children: correlation between plasma levels of three soluble inducible adhesion molecules and TNF-α. Acta. Trop.102(1), 20–28 (2007).
  • Yeo TW, Lampah DA, Gitawati R et al. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc. Natl Acad. Sci. USA105(44), 17097–17102 (2008).
  • Erdman LK, Dhabangi A, Musoke C et al. Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: A retrospective case–control study. PLoS One6(2), e17440 (2011).
  • Jakobsen PH, Morris-Jones S, Ronn A et al. Increased plasma concentrations of sICAM-1, sVCAM-1 and sELAM-1 in patients with Plasmodium falciparum or P. vivax malaria and association with disease severity. Immunology83(4), 665–669 (1994).
  • Conroy AL, Phiri H, Hawkes M et al. Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case–control study. PLoS One5(12), e15291 (2010).
  • Hickey MJ, Kubes P. Intravascular immunity: the host–pathogen encounter in blood vessels. Nat. Rev. Immunol.9(5), 364–375 (2009).
  • Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol.7(10), 803–815 (2007).
  • Moncada S, Higgs A. The L-arginine–nitric oxide pathway. N. Engl. J. Med.329(27), 2002–2012 (1993).
  • De Caterina R, Libby P, Peng HB et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J. Clin. Invest.96(1), 60–68 (1995).
  • Serirom S, Raharjo WH, Chotivanich K, Loareesuwan S, Kubes P, Ho M. Anti-adhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow. Am. J. Pathol.162(5), 1651–1660 (2003).
  • Matsushita K, Morrell CN, Cambien B et al. Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor. Cell115(2), 139–150 (2003).
  • Anstey NM, Weinberg JB, Hassanali MY et al. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J. Exp. Med.184(2), 557–567 (1996).
  • Lopansri BK, Anstey NM, Weinberg JB et al. Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production. Lancet361(9358), 676–678 (2003).
  • Yeo TW, Lampah DA, Gitawati R et al. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. J. Exp. Med.204(11), 2693–2704 (2007).
  • Yeo TW, Lampah DA, Tjitra E et al. Increased asymmetric dimethylarginine in severe falciparum malaria: association with impaired nitric oxide bioavailability and fatal outcome. PLoS Pathog.6(4), e1000868 (2010).
  • Yeo TW, Lampah DA, Tjitra E et al. Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria. J. Infect. Dis.200(10), 1522–1529 (2009).
  • DiBlasi RM, Myers TR, Hess DR. Evidence-based clinical practice guideline: inhaled nitric oxide for neonates with acute hypoxic respiratory failure. Respir. Care55(12), 1717–1745 (2010).
  • Gramaglia I, Sobolewski P, Meays D et al. Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat. Med.12(12), 1417–1422 (2006).
  • Cabrales P, Zanini GM, Meays D, Frangos JA, Carvalho LJ. Nitric oxide protection against murine cerebral malaria is associated with improved cerebral microcirculatory physiology. J. Infect. Dis.203(10), 1454–1463 (2011).
  • Yeo TW, Lampah DA, Gitawati R et al. Recovery of endothelial function in severe falciparum malaria: relationship with improvement in plasma L-arginine and blood lactate concentrations. J. Infect. Dis.198(4), 602–608 (2008).
  • Kim H, Higgins S, Liles WC, Kain KC. Endothelial activation and dysregulation in malaria: a potential target for novel therapeutics. Curr. Opin. Hematol.18(3), 177–185 (2011).
  • Li J-J, Huang Y-Q, Basch R, Karpatkin S. Thrombin induces the release of angiopoietin-1 from platelets. Thromb. Haemost.85, 204–206 (2001).
  • Suri C, Jones PF, Patan S et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell87(7), 1171–1180 (1996).
  • Partanen J, Armstrong E, Makela TP et al. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol. Cell. Biol.12(4), 1698–1707 (1992).
  • Fukuhara S, Sako K, Minami T et al. Differential function of Tie2 at cell–cell contacts and cell–substratum contacts regulated by angiopoietin-1. Nat. Cell. Biol.10(5), 513–526 (2008).
  • Saharinen P, Eklund L, Miettinen J et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts. Nat. Cell Biol.10(5), 527–537 (2008).
  • Kim I, Moon S-O, Park SK, Chae SW, Koh GY. Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression. Circ. Res.89(6), 477–479 (2001).
  • Klabunde J, Uhlemann AC, Tebo AE et al. Recognition of Plasmodium falciparum proteins by mannan-binding lectin, a component of the human innate immune system. Parasitol. Res.88(2), 113–117 (2002).
  • Fiedler U, Scharpfenecker M, Koidl S et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel–Palade bodies. Blood103(11), 4150–4156 (2004).
  • Maisonpierre PC, Suri C, Jones PF et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science277(5322), 55–60 (1997).
  • Reiss Y, Droste J, Heil M et al. Angiopoietin-2 impairs revascularization after limb ischemia. Circ. Res.101(1), 88–96 (2007).
  • Conroy AL, Lafferty EI, Lovegrove FE et al. Whole blood angiopoietin-1 and -2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria. Malar. J.8(1), 295 (2009).
  • Lovegrove FE, Tangpukdee N, Opoka RO et al. Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS One4(3), e4912 (2009).
  • Kim DH, Jung YJ, Lee AS et al. COMP-angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury. Kidney Int.76(11), 1180–1191 (2009).
  • Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med.4(9), e269 (2007).
  • Thurston G, Rudge JS, Ioffe E et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat. Med.6(4), 460–463 (2000).
  • Falcon BL, Hashizume H, Koumoutsakos P et al. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am. J. Pathol.175(5), 2159–2170 (2009).
  • Oliner J, Min H, Leal J et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell6(5), 507–516 (2004).
  • van der Heijden M, van Nieuw Amerongen GP, Chedamni S, van Hinsbergh VW, Johan Groeneveld AB. The angiopoietin–Tie2 system as a therapeutic target in sepsis and acute lung injury. Expert. Opin. Ther. Targets13(1), 39–53 (2009).
  • Nottebaum AF, Cagna G, Winderlich M et al. VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF. J. Exp. Med.205(12), 2929–2945 (2008).
  • Eriksson A, Cao R, Roy J et al. Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. Circulation107(11), 1532–1538 (2003).
  • Matsushita K, Yamakuchi M, Morrell CN et al. Vascular endothelial growth factor regulation of Weibel–Palade-body exocytosis. Blood105(1), 207–214 (2005).
  • Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J. Biol. Chem.274(22), 15732–15739 (1999).
  • Findley CM, Cudmore MJ, Ahmed A, Kontos CD. VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling. Arterioscler. Thromb. Vasc. Biol.27(12), 2619–2626 (2007).
  • Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-κ B activation in endothelial cells. J. Biol. Chem.276(10), 7614–7620 (2001).
  • Casals-Pascual C, Idro R, Gicheru N et al. High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria. Proc. Natl Acad. Sci. USA105(7), 2634–2639 (2008).
  • Epiphanio S, Campos MG, Pamplona A et al. VEGF promotes malaria-associated acute lung injury in mice. PLoS Pathog.6(5), e1000916 (2010).
  • Jain V, Armah HB, Tongren JE et al. Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar. J.7, 83 (2008).
  • Balachandar S, Katyal A. Peroxisome proliferator activating receptor (PPAR) in cerebral malaria (CM): a novel target for an additional therapy. Eur. J. Clin. Microbiol. Infect. Dis.30(4), 483–498 (2011).
  • Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science294(5548), 1866–1870 (2001).
  • Berger J, Moller DE. The mechanisms of action of PPARs. Ann. Rev. Med.53, 409–435 (2002).
  • Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm. Res.49(10), 497–505 (2000).
  • Zandbergen F, Plutzky J. PPARα in atherosclerosis and inflammation. Biochim. Biophys. Acta.1771(8), 972–982 (2007).
  • Ramirez SH, Heilman D, Morsey B, Potula R, Haorah J, Persidsky Y. Activation of peroxisome proliferator-activated receptor γ (PPARγ) suppresses ρ GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes. J. Immunol.180(3), 1854–1865 (2008).
  • Huang W, Eum SY, Andras IE, Hennig B, Toborek M. PPARα and PPARγ attenuate HIV-induced dysregulation of tight junction proteins by modulations of matrix metalloproteinase and proteasome activities. FASEB J.23(5), 1596–1606 (2009).
  • Ogasawara N, Kojima T, Go M et al. PPARγ agonists upregulate the barrier function of tight junctions via a PKC pathway in human nasal epithelial cells. Pharmacol. Res.61(6), 489–498.
  • Calnek DS, Mazzella L, Roser S, Roman J, Hart CM. Peroxisome proliferator-activated receptor γ ligands increase release of nitric oxide from endothelial cells. Arterioscler. Thromb. Vasc. Biol.23(1), 52–57 (2003).
  • Dobrian AD, Schriver SD, Khraibi AA, Prewitt RL. Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. Hypertension43(1), 48–56 (2004).
  • Boyle JG, Logan PJ, Ewart MA et al. Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase. J. Biol. Chem.283(17), 11210–11217 (2008).
  • Perampaladas K, Parker JD, Gori T. The impact of rosiglitazone on nitric oxide bioavailability and endothelial function. Clin. Hemorheol. Microcirc.45(2–4), 325–328 (2010).
  • Serghides L, Patel SN, Ayi K et al. Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria. J. Infect. Dis.199(10), 1536–1545 (2009).
  • Boggild AK, Krudsood S, Patel SN et al. Use of peroxisome proliferator-activated receptor γ agonists as adjunctive treatment for Plasmodium falciparum malaria: a randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis.49(6), 841–849 (2009).
  • Shanks GD. Are studies on severe malaria still possible? Clin. Infect. Dis.49(6), 850–851 (2009).
  • Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med.356(24), 2457–2471 (2007).
  • Brines M, Grasso G, Fiordaliso F et al. Erythropoietin mediates tissue protection through an erythropoietin and common β-subunit heteroreceptor. Proc. Natl Acad. Sci. USA101(41), 14907–14912 (2004).
  • Martinez-Estrada OM, Rodriguez-Millan E, Gonzalez-De Vicente E, Reina M, Vilaro S, Fabre M. Erythropoietin protects the in vitro blood–brain barrier against VEGF-induced permeability. Eur. J. Neurosci.18(9), 2538–2544 (2003).
  • Grasso G, Sfacteria A, Meli F, Fodale V, Buemi M, Iacopino DG. Neuroprotection by erythropoietin administration after experimental traumatic brain injury. Brain Res.1182, 99–105 (2007).
  • Villa P, Bigini P, Mennini T et al. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J. Exp. Med.198(6), 971–975 (2003).
  • Brines ML, Ghezzi P, Keenan S et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc. Natl Acad. Sci. USA97(19), 10526–10531 (2000).
  • Sakanaka M, Wen TC, Matsuda S et al.In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl Acad. Sci. USA95(8), 4635–4640 (1998).
  • Medana IM, Day NP, Hien TT, White NJ, Turner GD. Erythropoietin and its receptors in the brainstem of adults with fatal falciparum malaria. Malar. J.8, 261 (2009).
  • Bienvenu AL, Ferrandiz J, Kaiser K, Latour C, Picot S. Artesunate–erythropoietin combination for murine cerebral malaria treatment. Acta. Trop.106(2), 104–108 (2008).
  • Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals JA. Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar. J.7, 3 (2008).
  • Kaiser K, Texier A, Ferrandiz J et al. Recombinant human erythropoietin prevents the death of mice during cerebral malaria. J. Infect. Dis.193(7), 987–995 (2006).
  • Toba H, Morishita M, Tojo C et al. Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta. Eur. J. Pharmacol.656(1–3), 81–87 (2011).
  • Ehrenreich H, Weissenborn K, Prange H et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke40(12), e647–e656 (2009).
  • Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol.4(8), 459–460 (2003).
  • Siren AL, Fasshauer T, Bartels C, Ehrenreich H. Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics6(1), 108–127 (2009).
  • Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ.11(Suppl. 1), S37–S44 (2004).
  • Wassmer SC, Moxon CA, Taylor T, Grau GE, Molyneux ME, Craig AG. Vascular endothelial cells cultured from patients with cerebral or uncomplicated malaria exhibit differential reactivity to TNF. Cell Microbiol.13(2), 198–209 (2011).
  • Dondorp AM, Silamut K, Charunwatthana P et al. Levamisole inhibits sequestration of infected red blood cells in patients with falciparum malaria. J. Infect. Dis.196(3), 460–466 (2007).
  • McGilvray ID, Serghides L, Kapus A, Rotstein OD, Kain KC. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood96(9), 3231–3240 (2000).
  • Serghides L, Smith TG, Patel SN, Kain KC. CD36 and malaria: friends or foes? Trends Parasitol.19(10), 461–469 (2003).
  • Chilongola J, Balthazary S, Mpina M, Mhando M, Mbugi E. CD36 deficiency protects against malarial anaemia in children by reducing Plasmodium falciparum-infected red blood cell adherence to vascular endothelium. Trop. Med. Int. Health14(7), 810–816 (2009).
  • Beeson JG, Rogerson SJ, Cooke BM et al. Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria. Nat. Med.6(1), 86–90 (2000).
  • Carlson J, Ekre HP, Helmby H, Gysin J, Greenwood BM, Wahlgren M. Disruption of Plasmodium falciparum erythrocyte rosettes by standard heparin and heparin devoid of anticoagulant activity. Am. J. Trop. Med. Hyg.46(5), 595–602 (1992).
  • Rogerson SJ, Reeder JC, Al-Yaman F, Brown GV. Sulfated glycoconjugates as disrupters of Plasmodium falciparum erythrocyte rosettes. Am. J. Trop. Med. Hyg.51(2), 198–203 (1994).
  • Evans SG, Morrison D, Kaneko Y, Havlik I. The effect of curdlan sulphate on development in vitro of Plasmodium falciparum. Trans. R. Soc. Trop. Med. Hyg.92(1), 87–89 (1998).
  • Juillerat A, Lewit-Bentley A, Guillotte M et al. Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition. Proc. Natl Acad. Sci. USA108(13), 5243–5248 (2011).
  • Newton CR, Krishna S. Severe falciparum malaria in children: current understanding of pathophysiology and supportive treatment. Pharmacol. Ther.79(1), 1–53 (1998).
  • Yeo TW, Rooslamiati I, Gitawati R et al. Pharmacokinetics of L-arginine in adults with moderately severe malaria. Antimicrob. Agents Chemother.52(12), 4381–4387 (2008).
  • Picot S, Bienvenu AL, Konate S et al. Safety of epoietin β-quinine drug combination in children with cerebral malaria in Mali. Malar. J.8, 169 (2009).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.