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Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream

It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei AN...

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Autores principales: Hoffmann, Angelika, Pfeil, Johannes, Alfonso, Julieta, Kurz, Felix T., Sahm, Felix, Heiland, Sabine, Monyer, Hannah, Bendszus, Martin, Mueller, Ann-Kristin, Helluy, Xavier, Pham, Mirko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786214/
https://www.ncbi.nlm.nih.gov/pubmed/26964100
http://dx.doi.org/10.1371/journal.ppat.1005470
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author Hoffmann, Angelika
Pfeil, Johannes
Alfonso, Julieta
Kurz, Felix T.
Sahm, Felix
Heiland, Sabine
Monyer, Hannah
Bendszus, Martin
Mueller, Ann-Kristin
Helluy, Xavier
Pham, Mirko
author_facet Hoffmann, Angelika
Pfeil, Johannes
Alfonso, Julieta
Kurz, Felix T.
Sahm, Felix
Heiland, Sabine
Monyer, Hannah
Bendszus, Martin
Mueller, Ann-Kristin
Helluy, Xavier
Pham, Mirko
author_sort Hoffmann, Angelika
collection PubMed
description It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5±1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2±0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5±2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis.
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spelling pubmed-47862142016-03-23 Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream Hoffmann, Angelika Pfeil, Johannes Alfonso, Julieta Kurz, Felix T. Sahm, Felix Heiland, Sabine Monyer, Hannah Bendszus, Martin Mueller, Ann-Kristin Helluy, Xavier Pham, Mirko PLoS Pathog Research Article It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5±1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2±0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5±2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis. Public Library of Science 2016-03-10 /pmc/articles/PMC4786214/ /pubmed/26964100 http://dx.doi.org/10.1371/journal.ppat.1005470 Text en © 2016 Hoffmann et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hoffmann, Angelika
Pfeil, Johannes
Alfonso, Julieta
Kurz, Felix T.
Sahm, Felix
Heiland, Sabine
Monyer, Hannah
Bendszus, Martin
Mueller, Ann-Kristin
Helluy, Xavier
Pham, Mirko
Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream
title Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream
title_full Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream
title_fullStr Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream
title_full_unstemmed Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream
title_short Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream
title_sort experimental cerebral malaria spreads along the rostral migratory stream
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786214/
https://www.ncbi.nlm.nih.gov/pubmed/26964100
http://dx.doi.org/10.1371/journal.ppat.1005470
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