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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 TMTTM isobaric 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.

SUBMITTER: Tiberti N

PROVIDER: S-EPMC5137300 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Exploring experimental cerebral malaria pathogenesis through the characterisation of host-derived plasma microparticle protein content.

Tiberti Natalia N Latham Sharissa L SL Bush Stephen S Cohen Amy A Opoka Robert O RO John Chandy C CC Juillard Annette A Grau Georges E GE Combes Valéry V

Scientific reports 20161205

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 fi ...[more]

PMID: 27917875

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Project description:Cerebral malaria (CM) is a severe complication of a Plasmodium falciparum infection and is still responsible for a high number of deaths and long term disabilities in children in sub-Saharan Africa. The pathogenesis of this syndrome remains incompletely understood but a number of mechanisms and effectors have been proposed, including plasma microparticles (MP). These submicron vesicles released by potentially all cells carry proteins and nucleic acids derived from the mother cell. In CM, their numbers are increased in 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 characterising this content could help in better understand CM pathogenesis. Using qualitative and quantitative high-throughput proteomics we compared MP proteins from non-infected mice and mice infected with P. berghei ANKA at two different stages of infection, i.e., pre-clinical phase and full blown syndrome. Overall, we identified 368 proteins, 60 of which were differentially expressed, as determined by quantitative comparison using the TMT® isobaric labelling. The analysis with Ingenuity® IPA highlighted important networks significantly represented among the proteins over-expressed (n=42) or identified only (n=21) in ECM, comprising mechanisms already proposed to be involved in CM, such as endothelial activation. Two proteins of interest, carbonic anhydrase I (CA-I) and S100A8, were verified by western blot on newly collected MP samples from DBA/1 (n=16) and C57BL/6 (n=8) mice, and confirmed to be associated with ECM MP. These results demonstrate that MP protein cargo represents a novel ECM pathogenic trait to consider in the understanding of CM pathogenesis. The identification of the cellular source of MP containing proteins associated to the disease state will contribute to further understanding their involvement in CM.

Project description:Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8(+) T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45(hi) CD8(+) T cells, ICAM-1(+) macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8(+) T cells and ICAM(+) macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension.

Dataset Information

Exploring experimental cerebral malaria pathogenesis through the characterisation of host-derived plasma microparticle protein content.

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Exploring experimental cerebral malaria pathogenesis through the characterisation of host-derived plasma microparticle protein content.

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