Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria

Authors: Kyle D. Wilson, Lorenzo F. Ochoa, Olivia D. Solomon, Rahul Pal, Sandra M. Cardona, Victor H. Carpio, Philip H. Keiser, Astrid E. Cardona, Gracie Vargas, Robin Stephens

Published in: Journal of Neuroinflammation | Issue 1/2018

Login to get access

Abstract

Background

Cerebral malaria (CM) is the most lethal outcome of Plasmodium infection. There are clear correlations between expression of inflammatory cytokines, severe coagulopathies, and mortality in human CM. However, the mechanisms intertwining the coagulation and inflammation pathways, and their roles in CM, are only beginning to be understood. In mice with T cells deficient in the regulatory cytokine IL-10 (IL-10 KO), infection with Plasmodium chabaudi leads to a hyper-inflammatory response and lethal outcome that can be prevented by anti-TNF treatment. However, inflammatory T cells are adherent within the vasculature and not present in the brain parenchyma, suggesting a novel form of cerebral inflammation. We have previously documented behavioral dysfunction and microglial activation in infected IL-10 KO animals suggestive of neurological involvement driven by inflammation. In order to understand the relationship of intravascular inflammation to parenchymal dysfunction, we studied the congestion of vessels with leukocytes and fibrin(ogen) and the relationship of glial cell activation to congested vessels in the brains of P. chabaudi-infected IL-10 KO mice.

Methods

Using immunofluorescence microscopy, we describe severe thrombotic congestion in these animals. We stained for immune cell surface markers (CD45, CD11b, CD4), fibrin(ogen), microglia (Iba-1), and astrocytes (GFAP) in the brain at the peak of behavioral symptoms. Finally, we investigated the roles of inflammatory cytokine tumor necrosis factor (TNF) and coagulation on the pathology observed using neutralizing antibodies and low-molecular weight heparin to inhibit both inflammation and coagulation, respectively.

Results

Many blood vessels in the brain were congested with thrombi containing adherent leukocytes, including CD4 T cells and monocytes. Despite containment of the pathogen and leukocytes within the vasculature, activated microglia and astrocytes were prevalent in the parenchyma, particularly clustered near vessels with thrombi. Neutralization of TNF, or the coagulation cascade, significantly reduced both thrombus formation and gliosis in P. chabaudi-infected IL-10 KO mice.

Conclusions

These findings support the contribution of cytokines, coagulation, and leukocytes within the brain vasculature to neuropathology in malaria infection. Strikingly, localization of inflammatory leukocytes within intravascular clots suggests a mechanism for interaction between the two cascades by which cytokines drive local inflammation without considerable cellular infiltration into the brain parenchyma.
Appendix
Available only for authorised users
Literature
1.
2.
Seydel KB, Kampondeni SD, Valim C, Potchen MJ, Milner DA, Muwalo FW, Birbeck GL, Bradley WG, Fox LL, Glover SJ, et al. Brain swelling and death in children with cerebral malaria. N Engl J Med. 2015;372:1126–37.CrossRefPubMedPubMedCentral
3.
Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol. 2005;4:827–40.CrossRefPubMed
4.
Idro R, Kakooza-Mwesige A, Balyejjussa S, Mirembe G, Mugasha C, Tugumisirize J, Byarugaba J. Severe neurological sequelae and behaviour problems after cerebral malaria in Ugandan children. BMC Res Notes. 2010;3:104.CrossRefPubMedPubMedCentral
5.
Armah HB, Wilson NO, Sarfo BY, Powell MD, Bond VC, Anderson W, Adjei AA, Gyasi RK, Tettey Y, Wiredu EK, et al. Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children. Malar J. 2007;6:147.CrossRefPubMedPubMedCentral
6.
McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994;371:508–10.CrossRefPubMed
7.
Ouma C, Davenport GC, Were T, Otieno MF, Hittner JB, Vulule JM, Martinson J, Ong’echa JM, Ferrell RE, Perkins DJ. Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production. Hum Genet. 2008;124:515–24.CrossRefPubMedPubMedCentral
8.
Burt RA, Baldwin TM, Marshall VM, Foote SJ. Temporal expression of an H2-linked locus in host response to mouse malaria. Immunogenetics. 1999;50:278–85.CrossRefPubMed
9.
Knight JC, Udalova I, Hill AVS, Greenwood BM, Peshu N, Marsh K, Kwiatkowski D. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999;22:145.CrossRefPubMed
10.
Fortin A, Stevenson MM, Gros P. Complex genetic control of susceptibility to malaria in mice. Genes Immun. 2002;3:177–86.CrossRefPubMed
11.
Amante FH, Haque A, Stanley AC, Rivera Fde L, Randall LM, Wilson YA, Yeo G, Pieper C, Crabb BS, de Koning-Ward TF, et al. Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria. J Immunol. 2010;185:3632–42.CrossRefPubMed
12.
Chakravorty SJ, Carret C, Nash GB, Ivens A, Szestak T, Craig AG. Altered phenotype and gene transcription in endothelial cells, induced by Plasmodium falciparum-infected red blood cells: pathogenic or protective? Int J Parasitol. 2007;37:975–87.CrossRefPubMedPubMedCentral
13.
Palomo J, Reverchon F, Piotet J, Besnard AG, Couturier-Maillard A, Maillet I, Tefit M, Erard F, Mazier D, Ryffel B, Quesniaux VF. Critical role of IL-33 receptor ST2 in experimental cerebral malaria development. Eur J Immunol. 2015;45:1354–65.CrossRefPubMed
14.
Li C, Sanni LA, Omer F, Riley E, Langhorne J. Pathology of Plasmodium chabaudi chabaudi infection and mortality in interleukin-10-deficient mice are ameliorated by anti-tumor necrosis factor alpha and exacerbated by anti-transforming growth factor beta antibodies. Infect Immun. 2003;71:4850–6.CrossRefPubMedPubMedCentral
15.
Sanni LA, Jarra W, Li C, Langhorne J. Cerebral edema and cerebral hemorrhages in interleukin-10-deficient mice infected with Plasmodium chabaudi. Infect Immun. 2004;72:3054–8.CrossRefPubMedPubMedCentral
16.
Wilson KD, Stutz SJ, Ochoa LF, Valbuena GA, Cravens PD, Dineley KT, Vargas G, Stephens R. Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi. Malar J. 2016;15:428.CrossRefPubMedPubMedCentral
17.
Mota MM, Jarra W, Hirst E, Patnaik PK, Holder AA. Plasmodium chabaudi-infected erythrocytes adhere to CD36 and bind to microvascular endothelial cells in an organ-specific way. Infect Immun. 2000;68:4135–44.CrossRefPubMedPubMedCentral
18.
Brugat T, Cunningham D, Sodenkamp J, Coomes S, Wilson M, Spence PJ, Jarra W, Thompson J, Scudamore C, Langhorne J. Sequestration and histopathology in Plasmodium chabaudi malaria are influenced by the immune response in an organ-specific manner. Cell Microbiol. 2014;16:687–700.CrossRefPubMed
19.
Cunningham DA, Lin JW, Brugat T, Jarra W, Tumwine I, Kushinga G, Ramesar J, Franke-Fayard B, Langhorne J. ICAM-1 is a key receptor mediating cytoadherence and pathology in the Plasmodium chabaudi malaria model. Malar J. 2017;16:185.CrossRefPubMedPubMedCentral
20.
Dorovini-Zis K, Schmidt K, Huynh H, Fu W, Whitten RO, Milner D, Kamiza S, Molyneux M, Taylor TE. The neuropathology of fatal cerebral malaria in Malawian children. Am J Pathol. 2011;178:2146–58.CrossRefPubMedPubMedCentral
21.
Ponsford MJ, Medana IM, Prapansilp P, Hien TT, Lee SJ, Dondorp AM, Esiri MM, Day NP, White NJ, Turner GD. Sequestration and microvascular congestion are associated with coma in human cerebral malaria. J Infect Dis. 2012;205:663–71.CrossRefPubMed
22.
Jensen AT, Magistrado P, Sharp S, Joergensen L, Lavstsen T, Chiucchiuini A, Salanti A, Vestergaard LS, Lusingu JP, Hermsen R, et al. Plasmodium falciparum associated with severe childhood malaria preferentially expresses PfEMP1 encoded by group A var genes. J Exp Med. 2004;199:1179–90.CrossRefPubMedPubMedCentral
23.
Bernabeu M, Danziger SA, Avril M, Vaz M, Babar PH, Brazier AJ, Herricks T, Maki JN, Pereira L, Mascarenhas A, et al. Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass. Proc Natl Acad Sci U S A. 2016;113:E3270–9.CrossRefPubMedPubMedCentral
24.
Lavstsen T, Turner L, Saguti F, Magistrado P, Rask TS, Jespersen JS, Wang CW, Berger SS, Baraka V, Marquard AM, et al. Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. Proc Natl Acad Sci U S A. 2012;109:E1791–800.CrossRefPubMedPubMedCentral
25.
Avril M, Tripathi AK, Brazier AJ, Andisi C, Janes JH, Soma VL, Sullivan DJ Jr, Bull PC, Stins MF, Smith JD. A restricted subset of var genes mediates adherence of Plasmodium falciparum-infected erythrocytes to brain endothelial cells. Proc Natl Acad Sci U S A. 2012;109:E1782–90.CrossRefPubMedPubMedCentral
26.
Grau GE, Piguet PF, Vassalli P, Lambert PH. Tumor-necrosis factor and other cytokines in cerebral malaria: experimental and clinical data. Immunol Rev. 1989;112:49–70.CrossRefPubMed
27.
Kwiatkowski DP, Luoni G. Host genetic factors in resistance and susceptibility to malaria. Parassitologia. 2006;48:450–67.PubMed
28.
May J, Lell B, Luty AJ, Meyer CG, Kremsner PG. Plasma interleukin-10: tumor necrosis factor (TNF)-alpha ratio is associated with TNF promoter variants and predicts malarial complications. J Infect Dis. 2000;182:1570–3.CrossRefPubMed
29.
Ho M, Schollaardt T, Snape S, Looareesuwan S, Suntharasamai P, White NJ. Endogenous interleukin-10 modulates proinflammatory response in Plasmodium falciparum malaria. J Infect Dis. 1998;178:520–5.CrossRefPubMed
30.
Freitas do Rosario AP, Langhorne J. T cell-derived IL-10 and its impact on the regulation of host responses during malaria. Int J Parasitol. 2012;42:549–55.CrossRefPubMed
31.
Li C, Corraliza I, Langhorne J. A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice. Infect Immun. 1999;67:4435–42.PubMedPubMedCentral
32.
Freitas do Rosario AP, Lamb T, Spence P, Stephens R, Lang A, Roers A, Muller W, O'Garra A, Langhorne J. IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J Immunol. 2012;188:1178–90.CrossRefPubMed
33.
Couper KN, Blount DG, Wilson MS, Hafalla JC, Belkaid Y, Kamanaka M, Flavell RA, de Souza JB, Riley EM. IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection. PLoS Pathog. 2008;4:e1000004.CrossRefPubMedPubMedCentral
34.
Turner GD, Morrison H, Jones M, Davis TM, Looareesuwan S, Buley ID, Gatter KC, Newbold CI, Pukritayakamee S, Nagachinta B, 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. 1994;145:1057–69.PubMedPubMedCentral
35.
MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985;119:385–401.PubMedPubMedCentral
36.
37.
Spitz S. The pathology of acute falciparum malaria. Mil Surg. 1946;99:555–72.PubMed
38.
Berendt AR, Tumer GDH, Newbold CI. Cerebral malaria: the sequestration hypothesis. Parasitol Today. 1994;10:412–4.CrossRefPubMed
39.
Pongponratn E, Turner GD, Day NP, Phu NH, Simpson JA, Stepniewska K, Mai NT, Viriyavejakul P, Looareesuwan S, Hien TT, et al. An ultrastructural study of the brain in fatal Plasmodium falciparum malaria. Am J Trop Med Hyg. 2003;69:345–59.PubMedCrossRef
40.
41.
Lewallen S, Bakker H, Taylor TE, Wills BA, Courtright P, Molyneux ME. Retinal findings predictive of outcome in cerebral malaria. Trans R Soc Trop Med Hyg. 1996;90:144–6.CrossRefPubMed
42.
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. Am J Trop Med Hyg. 1994;51:642–7.CrossRefPubMed
43.
Franke-Fayard B, Janse CJ, Cunha-Rodrigues M, Ramesar J, Buscher P, Que I, Lowik C, Voshol PJ, den Boer MA, van Duinen SG, et al. Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration. Proc Natl Acad Sci U S A. 2005;102:11468–73.CrossRefPubMedPubMedCentral
44.
Bridges DJ, Bunn J, van Mourik JA, Grau G, Preston RJ, Molyneux M, Combes V, O'Donnell JS, de Laat B, Craig A. Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings. Blood. 2010;115:1472–4.CrossRefPubMed
45.
Moxon CA, Wassmer SC, Milner DA, Jr., Chisala NV, Taylor TE, Seydel KB, Molyneux ME, Faragher B, Esmon CT, Downey C, et al: Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. Blood 2013, 122:842–851.
46.
O'Regan N, Gegenbauer K, O'Sullivan JM, Maleki S, Brophy TM, Dalton N, Chion A, Fallon PG, Grau GE, Budde U, et al. A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria. Blood. 2016;127:1192–201.CrossRefPubMedPubMedCentral
47.
Sun G, Chang WL, Li J, Berney SM, Kimpel D, van der Heyde HC. Inhibition of platelet adherence to brain microvasculature protects against severe Plasmodium berghei malaria. Infect Immun. 2003;71:6553–61.CrossRefPubMedPubMedCentral
48.
Moxon CA, Chisala NV, Mzikamanda R, MacCormick I, Harding S, Downey C, Molyneux M, Seydel KB, Taylor TE, Heyderman RS, Toh CH. Laboratory evidence of disseminated intravascular coagulation is associated with a fatal outcome in children with cerebral malaria despite an absence of clinically evident thrombosis or bleeding. J Thromb Haemost. 2015;13:1653–64.CrossRefPubMedPubMedCentral
49.
Rampengan TH. Cerebral malaria in children. Comparative study between heparin, dexamethasone and placebo. Paediatrica Indonesiana. 1991;31:59–66.PubMed
50.
Munir M, Tjandra H, Rampengan TH, Mustadjab I, Wulur FH. Heparin in the treatment of cerebral malaria. Paediatr Indones. 1980;20:47–50.PubMed
51.
Reid HA, Sucharit P. Ancrod, heparin, and -aminocaproic acid in simian Knowlesi malaria. Lancet. 1972;2:1110–2.CrossRefPubMed
52.
Stone WJ, Hanchett JE, Knepshield JH. Acute renal insufficiency due to falciparum malaria. Review of 42 cases. Arch Intern Med. 1972;129:620–8.CrossRefPubMed
53.
Grau GE, Craig AG. Cerebral malaria pathogenesis: revisiting parasite and host contributions. Future Microbiol. 2012;7:291–302.CrossRefPubMed
54.
Rogers DC, Fisher EM, Brown SD, Peters J, Hunter AJ, Martin JE. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome. 1997;8:711–3.CrossRefPubMed
55.
56.
Chung K, Wallace J, Kim S-Y, Kalyanasundaram S, Andalman AS, Davidson TJ, Mirzabekov JJ, Zalocusky KA, Mattis J, Denisin AK, et al. Structural and molecular interrogation of intact biological systems. Nature. 2013;497:332–7.CrossRefPubMedPubMedCentral
57.
Bertini R, Bianchi M, Villa P, Ghezzi P. Depression of liver drug metabolism and increase in plasma fibrinogen by interleukin 1 and tumor necrosis factor: a comparison with lymphotoxin and interferon. Int J Immunopharmacol. 1988;10:525–30.CrossRefPubMed
58.
59.
Blombäck B, Hessel B, Hogg D, Therkildsen L. A two-step fibrinogen—fibrin transition in blood coagulation. Nature. 1978;275:501–5.CrossRefPubMed
60.
Raut S, McEvoy F, Gaffney PJ. Development of an ELISA for the quantification of fibrin in canine tumours. Thromb Res. 1999;96:11–7.CrossRefPubMed
61.
Clemmensen I. Three new E-antigenic fibrinogen fractions found in a commercial plasmin preparation. Science Tools LKB Instr J. 1973;20:7–8.
62.
Medana IM, Chaudhri G, Chan-Ling T, Hunt NH. Central nervous system in cerebral malaria: ‘innocent bystander’ or active participant in the induction of immunopathology? Immunol Cell Biol. 2001;79:101–20.CrossRefPubMed
63.
Ridet JL, Privat A, Malhotra SK, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1997;20:570–7.CrossRefPubMed
64.
Haussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut. 2008;57:1156–65.CrossRefPubMed
65.
Yap GS, Stevenson MM. Blood transfusion alters the course and outcome of Plasmodium chabaudi AS infection in mice. Infect Immun. 1994;62:3761–5.PubMedPubMedCentral
66.
Brown H, Hien TT, Day N, Mai NT, Chuong LV, Chau TT, Loc PP, Phu NH, Bethell D, Farrar J, et al. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol. 1999;25:331–40.CrossRefPubMed
67.
Nacer A, Movila A, Baer K, Mikolajczak SA, Kappe SH, Frevert U. Neuroimmunological blood brain barrier opening in experimental cerebral malaria. PLoS Pathog. 2012;8:e1002982.CrossRefPubMedPubMedCentral
68.
Milner DA, Whitten RO, Kamiza S, Carr R, Liomba G, Dzamalala C, Seydel KB, Molyneux ME, Taylor TE. The systemic pathology of cerebral malaria in African children. Front Cell Infect Microbiol. 2014;4:104.
69.
70.
71.
Feintuch CM, Saidi A, Seydel K, Chen G, Goldman-Yassen A, Mita-Mendoza NK, Kim RS, Frenette PS, Taylor T, Daily JP. Activated neutrophils are associated with pediatric cerebral malaria vasculopathy in Malawian children. MBio. 2016;7:e01300–15.CrossRefPubMedPubMedCentral
72.
Hochman SE, Madaline TF, Wassmer SC, Mbale E, Choi N, Seydel KB, Whitten RO, Varughese J, Grau GE, Kamiza S, et al. Fatal pediatric cerebral malaria is associated with intravascular monocytes and platelets that are increased with HIV coinfection. MBio. 2015;6:e01390–15.CrossRefPubMedPubMedCentral
73.
Sampath S, Brazier AJ, Avril M, Bernabeu M, Vigdorovich V, Mascarenhas A, Gomes E, Sather DN, Esmon CT, Smith JD. Plasmodium falciparum adhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor. Cell Microbiol. 2015;17:1868–82.CrossRefPubMedPubMedCentral
74.
Desruisseaux MS, Gulinello M, Smith DN, Lee SC, Tsuji M, Weiss LM, Spray DC, Tanowitz HB. Cognitive dysfunction in mice infected with Plasmodium berghei strain ANKA. J Infect Dis. 2008;197:1621–7.CrossRefPubMedPubMedCentral
75.
Lackner P, Beer R, Heussler V, Goebel G, Rudzki D, Helbok R, Tannich E, Schmutzhard E. Behavioural and histopathological alterations in mice with cerebral malaria. Neuropathol Appl Neurobiol. 2006;32:177–88.CrossRefPubMed
76.
Lacerda-Queiroz N, Rodrigues DH, Vilela MC, Miranda AS, Amaral DC, Camargos ER, Carvalho LJ, Howe CL, Teixeira MM, Teixeira AL. Inflammatory changes in the central nervous system are associated with behavioral impairment in Plasmodium berghei (strain ANKA)-infected mice. Exp Parasitol. 2010;125:271–8.CrossRefPubMedPubMedCentral
77.
Nie CQ, Bernard NJ, Norman MU, Amante FH, Lundie RJ, Crabb BS, Heath WR, Engwerda CR, Hickey MJ, Schofield L, Hansen DS. IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection. PLoS Pathog. 2009;5:e1000369.CrossRefPubMedPubMedCentral
78.
Campanella GS, Tager AM, El Khoury JK, Thomas SY, Abrazinski TA, Manice LA, Colvin RA, Luster AD. 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. 2008;105:4814–9.CrossRefPubMedPubMedCentral
79.
Rudin W, Eugster HP, Bordmann G, Bonato J, Müller M, Yamage M, Ryffel B. Resistance to cerebral malaria in tumor necrosis factor-alpha/beta-deficient mice is associated with a reduction of intercellular adhesion molecule-1 up-regulation and T helper type 1 response. Am J Pathol. 1997;150:257–66.PubMedPubMedCentral
80.
Ampawong S, Chaisri U, Viriyavejakul P, Nontprasert A, Grau GE, Pongponratn E. Electron microscopic features of brain edema in rodent cerebral malaria in relation to glial fibrillary acidic protein expression. Int J Clin Exp Pathol. 2014;7:2056–67.PubMedPubMedCentral
81.
Ma N, Madigan MC, Chan-Ling T, Hunt NH. Compromised blood-nerve barrier, astrogliosis, and myelin disruption in optic nerves during fatal murine cerebral malaria. Glia. 1997;19:135–51.CrossRefPubMed
82.
Medana IM, Turner GDH. Human cerebral malaria and the blood–brain barrier. Int J Parasitol. 2006;36:555–68.CrossRefPubMed
83.
O'Sullivan JM, Preston RJ, O'Regan N, O'Donnell JS. Emerging roles for hemostatic dysfunction in malaria pathogenesis. Blood. 2016;127:2281–8.CrossRefPubMed
84.
Hearn J, Rayment N, Landon DN, Katz DR, de Souza JB. Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain microvasculature. Infect Immun. 2000;68:5364–76.CrossRefPubMedPubMedCentral
85.
Franke-Fayard B, Fonager J, Braks A, Khan SM, Janse CJ. Sequestration and tissue accumulation of human malaria parasites: can we learn anything from rodent models of malaria? PLoS Pathog. 2010;6:e1001032.CrossRefPubMedPubMedCentral
86.
Kwiatkowski D, Sambou I, Twumasi P, Greenwood BM, Hill AVS, Manogue KR, Cerami A, Castracane J, Brewster DR. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet. 1990;336:1201–4.CrossRefPubMed
87.
van Hensbroek MB, Palmer A, Onyiorah E, Schneider G, Jaffar S, Dolan G, Memming H, Frenkel J, Enwere G, Bennett S, et al. The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. J Infect Dis. 1996;174:1091–7.CrossRefPubMed
88.
Kwiatkowski D, Molyneux ME, Stephens S, Curtis N, Klein N, Pointaire P, Smit M, Allan R, Brewster DR, Grau GE, et al. Anti-TNF therapy inhibits fever in cerebral malaria. Q J Med. 1993;86:91–8.PubMed
89.
Severe and complicated malaria. World Health Organization Malaria Action Programme. Trans R Soc Trop Med Hyg. 1986;80 Suppl:3–50.
90.
Havlik I, Looareesuwan S, Vannaphan S, Wilairatana P, Krudsood S, Thuma PE, Kozbor D, Watanabe N, Kaneko Y. Curdlan sulphate in human severe/cerebral Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg. 2005;99:333–40.CrossRefPubMed
91.
92.
Sarkar S, Keswani T, Sengupta A, Mitra S, Bhattacharyya A. Differential modulation of glial cell mediated neuroinflammation in Plasmodium berghei ANKA infection by TGF beta and IL 6. Cytokine. 2017;99:249–59.CrossRefPubMed
93.
Reverchon F, Mortaud S, Sivoyon M, Maillet I, Laugeray A, Palomo J, Montecot C, Herzine A, Meme S, Meme W, et al. IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria. PLoS Pathog. 2017;13:e1006322.CrossRefPubMedPubMedCentral
94.
Capuccini B, Lin J, Talavera-Lopez C, Khan SM, Sodenkamp J, Spaccapelo R, Langhorne J. Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria. Sci Rep. 2016;6:39258.CrossRefPubMedPubMedCentral
95.
Schluesener HJ, Kremsner PG, Meyermann R. Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells. Acta Neuropathol. 1998;96:575–80.CrossRefPubMed
96.
Deininger MH, Kremsner PG, Meyermann R, Schluesener H. Macrophages/microglial cells in patients with cerebral malaria. Eur Cytokine Netw. 2002;13:173–85.PubMed
97.
Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, Harinasuta T. Dexamethasone proves deleterious in cerebral malaria. N Engl J Med. 1982;306:313–9.CrossRefPubMed
98.
Di Perri G, Di Perri HG, Monteiro GB, Bonora S, Hennig C, Cassatella M, Micciolo R, Vento S, Dusi S, Bassetti D, Concia E. Pentoxifylline as a supportive agent in the treatment of cerebral malaria in children. J Infect Dis. 1995;171:1317–22.CrossRefPubMed
99.
Hemmer CJ, Kern P, Holst FGE, 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. 1991;45:608–12.CrossRefPubMed
Metadata
Title
Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria
Authors
Kyle D. Wilson
Lorenzo F. Ochoa
Olivia D. Solomon
Rahul Pal
Sandra M. Cardona
Victor H. Carpio
Philip H. Keiser
Astrid E. Cardona
Gracie Vargas
Robin Stephens
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1207-4

Other articles of this Issue 1/2018

Journal of Neuroinflammation 1/2018 Go to the issue

Research

In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with [18F]DPA714 PET

Research

Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury

Research

Lentivirus-mediated overexpression of OTULIN ameliorates microglia activation and neuroinflammation by depressing the activation of the NF-κB signaling pathway in cerebral ischemia/reperfusion rats

Research

A mathematical model of neuroinflammation in severe clinical traumatic brain injury

Research

Decreased level of irisin, a skeletal muscle cell-derived myokine, is associated with post-stroke depression in the ischemic stroke population

Research

ITGB4 deficiency in bronchial epithelial cells directs airway inflammation and bipolar disorder-related behavior