title: Mechanisms of murine cerebral malaria: Multimodal imaging of altered cerebral metabolism and protein oxidation at hemorrhage sites.
abstract: Using a multimodal biospectroscopic approach, we settle several long-standing controversies over the molecular mechanisms that lead to brain damage in cerebral malaria, which is a major health concern in developing countries because of high levels of mortality and permanent brain damage. Our results provide the first conclusive evidence that important components of the pathology of cerebral malaria include peroxidative stress and protein oxidation within cerebellar gray matter, which are colocalized with elevated nonheme iron at the site of microhemorrhage. Such information could not be obtained previously from routine imaging methods, such as electron microscopy, fluorescence, and optical microscopy in combination with immunocytochemistry, or from bulk assays, where the level of spatial information is restricted to the minimum size of tissue that can be dissected. We describe the novel combination of chemical probe-free, multimodal imaging to quantify molecular markers of disturbed energy metabolism and peroxidative stress, which were used to provide new insights into understanding the pathogenesis of cerebral malaria. In addition to these mechanistic insights, the approach described acts as a template for the future use of multimodal biospectroscopy for understanding the molecular processes involved in a range of clinically important acute and chronic (neurodegenerative) brain diseases to improve treatment strategies.
authors.affiliation: School of Chemistry and Vibrational Spectroscopy Core Facility, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hackett
authors.affiliation: School of Chemistry and Vibrational Spectroscopy Core Facility, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Jade B
authors.identifier: 0000-0002-3530-7286
authors.initials: JB
authors.lastname: Aitken
authors.affiliation: Vascular Immunology Unit, Bosch Institute and School of Medical Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Fatima
authors.initials: F
authors.lastname: El-Assaad
authors.affiliation: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: McQuillan
authors.affiliation: School of Chemistry and Vibrational Spectroscopy Core Facility, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Elizabeth A
authors.identifier: 0000-0001-6318-7771
authors.initials: EA
authors.lastname: Carter
authors.affiliation: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.affiliation: Australian Synchrotron, 800 Blackburn Road, Clayton, Victoria 3168, Australia.
authors.forename: Mark J
authors.identifier: 0000-0003-1862-0649
authors.initials: MJ
authors.lastname: Tobin
authors.affiliation: Australian Synchrotron, 800 Blackburn Road, Clayton, Victoria 3168, Australia.
authors.forename: David
authors.identifier: 0000-0003-0409-9012
authors.initials: D
authors.lastname: Paterson
authors.affiliation: Australian Synchrotron, 800 Blackburn Road, Clayton, Victoria 3168, Australia.
authors.forename: Martin D
authors.identifier: 0000-0001-7731-6175
authors.initials: MD
authors.lastname: de Jonge
authors.affiliation: Institute for Environmental Research, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales 2234, Australia.
authors.forename: Rainer
authors.identifier: 0000-0003-2863-1560
authors.initials: R
authors.lastname: Siegele
authors.affiliation: Institute for Environmental Research, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales 2234, Australia.
authors.forename: David D
authors.identifier: 0000-0002-1209-9234
authors.initials: DD
authors.lastname: Cohen
authors.affiliation: Advanced Photon Source, Argonne National Laboratory, Argonne, IL 60439, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vogt
authors.affiliation: Vascular Immunology Unit, Bosch Institute and School of Medical Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Georges E
authors.initials: GE
authors.lastname: Grau
authors.affiliation: Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
authors.affiliation: School of Chemistry and Vibrational Spectroscopy Core Facility, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Peter A
authors.identifier: 0000-0002-3232-2720
authors.initials: PA
authors.lastname: Lay
keywords: Altered Cerebral Metabolism; Cerebral Malaria; FTIR Imaging; Molecular Mechanism; Multi-modal Imaging; Murine Model; Nuclear Microprobe; Protein Oxidation; X-ray Fluorecence Microscopy; resonance Raman Imaging
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