title: Exploring experimental cerebral malaria pathogenesis through the characterisation of host-derived plasma microparticle protein content.
abstract: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection responsible for thousands of deaths in children in sub-Saharan Africa. CM pathogenesis remains incompletely understood but a number of effectors have been proposed, including plasma microparticles (MP). MP numbers are increased in CM patients' circulation and, in the mouse model, they can be localised within inflamed vessels, suggesting their involvement in vascular damage. In the present work we define, for the first time, the protein cargo of MP during experimental cerebral malaria (ECM) with the overarching hypothesis that this characterisation could help understand CM pathogenesis. Using qualitative and quantitative high-throughput proteomics we compared MP proteins from non-infected and P. berghei ANKA-infected mice. More than 360 proteins were identified, 60 of which were differentially abundant, as determined by quantitative comparison using TMTTMisobaric labelling. Network analyses showed that ECM MP carry proteins implicated in molecular mechanisms relevant to CM pathogenesis, including endothelial activation. Among these proteins, the strict association of carbonic anhydrase I and S100A8 with ECM was verified by western blot on MP from DBA/1 and C57BL/6 mice. These results demonstrate that MP protein cargo represents a novel ECM pathogenic trait to consider in the understanding of CM pathogenesis.
authors.affiliation: School of Life Sciences, Faculty of Sciences, University of Technology Sydney, Australia.|Vascular Immunology Unit, Department of Pathology, The University of Sydney, Australia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tiberti
authors.affiliation: Vascular Immunology Unit, Department of Pathology, The University of Sydney, Australia.
authors.forename: Sharissa L
authors.initials: SL
authors.lastname: Latham
authors.affiliation: School of Mathematical and Physical Sciences, University of Technology Sydney, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Bush
authors.affiliation: Vascular Immunology Unit, Department of Pathology, The University of Sydney, Australia.
authors.forename: Amy
authors.initials: A
authors.lastname: Cohen
authors.affiliation: College of Health Sciences, Makerere University, Kampala, Uganda.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Opoka
authors.affiliation: Indiana University School of Medicine, Indianapolis, United States of America.|University of Minnesota, Minneapolis, United States of America.
authors.forename: Chandy C
authors.initials: CC
authors.lastname: John
authors.affiliation: Vascular Immunology Unit, Department of Pathology, The University of Sydney, Australia.
authors.forename: Annette
authors.initials: A
authors.lastname: Juillard
authors.affiliation: Vascular Immunology Unit, Department of Pathology, The University of Sydney, Australia.|La Jolla Infectious Diseases Institute, San Diego, CA, United States of America.
authors.forename: Georges E
authors.initials: GE
authors.lastname: Grau
authors.affiliation: School of Life Sciences, Faculty of Sciences, University of Technology Sydney, Australia.|Vascular Immunology Unit, Department of Pathology, The University of Sydney, Australia.|La Jolla Infectious Diseases Institute, San Diego, CA, United States of America.
authors.forename: Valéry
authors.initials: V
authors.lastname: Combes
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000473:pathology; D040501:Calgranulin A / Q000378:metabolism; D024401:Carbonic Anhydrase I / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000737:chemistry*; D002648:Child; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D016779:Malaria, Cerebral / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008855:Microscopy, Electron, Scanning; D010962:Plasmodium berghei; D010963:Plasmodium falciparum; D040901:Proteomics
chemical_list: D001798:Blood Proteins; D040501:Calgranulin A; C086145:S100a8 protein, mouse; D024401:Carbonic Anhydrase I