A Contrast Agent Recognizing Activated Platelets Reveals Murine Cerebral Malaria Pathology Undetectable by Conventional MRI

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2008 Feb 16

PMID 18274670

Citations 31

Authors

Constantin von Zur Muhlen

Nicola R Sibson

Karlheinz Peter

Sandra J Campbell

Panop Wilainam

Georges E Grau

Christoph Bode

Robin P Choudhury

Daniel C Anthony

Affiliations

Soon will be listed here.

Abstract

Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-alpha, but not IL-1beta or lymphotoxin-alpha (LT-alpha), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-alpha injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies.

Citing Articles

Contribution of Magnetic Resonance Imaging Studies to the Understanding of Cerebral Malaria Pathogenesis.

Comino Garcia-Munoz A, Varlet I, Grau G, Perles-Barbacaru T, Viola A Pathogens. 2025; 13(12.

PMID: 39770302 PMC: 11728472. DOI: 10.3390/pathogens13121042.

Diagnosis of cerebral malaria: Tools to reduce associated mortality.

Muppidi P, Wright E, Wassmer S, Gupta H Front Cell Infect Microbiol. 2023; 13:1090013.

PMID: 36844403 PMC: 9947298. DOI: 10.3389/fcimb.2023.1090013.

Tracking the immune response by MRI using biodegradable and ultrasensitive microprobes.

Martinez de Lizarrondo S, Jacqmarcq C, Naveau M, Navarro-Oviedo M, Pedron S, Adam A Sci Adv. 2022; 8(28):eabm3596.

PMID: 35857494 PMC: 9278862. DOI: 10.1126/sciadv.abm3596.

Platelets as Mediators of Neuroinflammation and Thrombosis.

Rawish E, Nording H, Munte T, Langer H Front Immunol. 2020; 11:548631.

PMID: 33123127 PMC: 7572851. DOI: 10.3389/fimmu.2020.548631.

Extracellular vesicle integrins act as a nexus for platelet adhesion in cerebral microvessels.

Bagi Z, Couch Y, Broskova Z, Perez-Balderas F, Yeo T, Davis S Sci Rep. 2019; 9(1):15847.

PMID: 31676801 PMC: 6825169. DOI: 10.1038/s41598-019-52127-3.

References

Grau G, Lou J . Experimental cerebral malaria: possible new mechanisms in the TNF-induced microvascular pathology. Soz Praventivmed. 1995; 40(1):50-7. DOI: 10.1007/BF01615662. View

Schwarz M, Meade G, Stoll P, Ylanne J, Bassler N, Chen Y . Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circ Res. 2006; 99(1):25-33. DOI: 10.1161/01.RES.0000232317.84122.0c. View

Sibson N, Blamire A, Perry V, Gauldie J, Styles P, Anthony D . TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway. Brain. 2002; 125(Pt 11):2446-59. DOI: 10.1093/brain/awf256. View

Bell M, Perry V . Adhesion molecule expression on murine cerebral endothelium following the injection of a proinflammagen or during acute neuronal degeneration. J Neurocytol. 1995; 24(9):695-710. DOI: 10.1007/BF01179819. View

Spuentrup E, Buecker A, Katoh M, Wiethoff A, Parsons Jr E, Botnar R . Molecular magnetic resonance imaging of coronary thrombosis and pulmonary emboli with a novel fibrin-targeted contrast agent. Circulation. 2005; 111(11):1377-82. DOI: 10.1161/01.CIR.0000158478.29668.9B. View

Schwarz M, Katagiri Y, Kotani M, Bassler N, Loeffler C, Bode C . Reversibility versus persistence of GPIIb/IIIa blocker-induced conformational change of GPIIb/IIIa (alphaIIbbeta3, CD41/CD61). J Pharmacol Exp Ther. 2003; 308(3):1002-11. DOI: 10.1124/jpet.103.058883. View

Bernardes-Silva M, Anthony D, Issekutz A, Perry V . Recruitment of neutrophils across the blood-brain barrier: the role of E- and P-selectins. J Cereb Blood Flow Metab. 2001; 21(9):1115-24. DOI: 10.1097/00004647-200109000-00009. View

Sun G, Chang W, Li J, Berney S, Kimpel D, van der Heyde H . Inhibition of platelet adherence to brain microvasculature protects against severe Plasmodium berghei malaria. Infect Immun. 2003; 71(11):6553-61. PMC: 219602. DOI: 10.1128/IAI.71.11.6553-6561.2003. View

Andersson P, Perry V, Gordon S . The acute inflammatory response to lipopolysaccharide in CNS parenchyma differs from that in other body tissues. Neuroscience. 1992; 48(1):169-86. DOI: 10.1016/0306-4522(92)90347-5. View

10.

Guerin C, Laterra J, Hruban R, Brem H, Drewes L, GOLDSTEIN G . The glucose transporter and blood-brain barrier of human brain tumors. Ann Neurol. 1990; 28(6):758-65. DOI: 10.1002/ana.410280606. View

11.

Marsh K, Snow R . Malaria transmission and morbidity. Parassitologia. 2000; 41(1-3):241-6. View

12.

Combes V, Rosenkranz A, Redard M, Pizzolato G, Lepidi H, Vestweber D . Pathogenic role of P-selectin in experimental cerebral malaria: importance of the endothelial compartment. Am J Pathol. 2004; 164(3):781-6. PMC: 1613268. DOI: 10.1016/S0002-9440(10)63166-5. View

13.

van der Heyde H, Nolan J, Combes V, Gramaglia I, Grau G . A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol. 2006; 22(11):503-8. DOI: 10.1016/j.pt.2006.09.002. View

14.

McAteer M, Schneider J, Ali Z, Warrick N, Bursill C, von Zur Muhlen C . Magnetic resonance imaging of endothelial adhesion molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide. Arterioscler Thromb Vasc Biol. 2007; 28(1):77-83. PMC: 3481783. DOI: 10.1161/ATVBAHA.107.145466. View

15.

Shapiro E, Skrtic S, Sharer K, Hill J, Dunbar C, Koretsky A . MRI detection of single particles for cellular imaging. Proc Natl Acad Sci U S A. 2004; 101(30):10901-6. PMC: 503717. DOI: 10.1073/pnas.0403918101. View

16.

Wassmer S, Combes V, Candal F, Juhan-Vague I, Grau G . Platelets potentiate brain endothelial alterations induced by Plasmodium falciparum. Infect Immun. 2005; 74(1):645-53. PMC: 1346683. DOI: 10.1128/IAI.74.1.645-653.2006. View

17.

Blamire A, Anthony D, Rajagopalan B, Sibson N, Perry V, Styles P . Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study. J Neurosci. 2000; 20(21):8153-9. PMC: 6772751. View

18.

Proescholdt M, Chakravarty S, Foster J, Foti S, Briley E, Herkenham M . Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience. 2002; 112(3):731-49. DOI: 10.1016/s0306-4522(02)00048-9. View

19.

Grau G, Mackenzie C, Carr R, Redard M, Pizzolato G, Allasia C . Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria. J Infect Dis. 2003; 187(3):461-6. DOI: 10.1086/367960. View

20.

Runge V, Schoerner W, Niendorf H, Laniado M, Koehler D, Claussen C . Initial clinical evaluation of gadolinium DTPA for contrast-enhanced magnetic resonance imaging. Magn Reson Imaging. 1985; 3(1):27-35. DOI: 10.1016/0730-725x(85)90006-2. View