Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream

PLoS Pathogens

Xavier Helluy¹  Felix T. Kurz²  Julieta Alfonso³  Sabine Heiland⁴  Ann-Kristin Mueller⁵  Angelika Hoffmann⁶  Hannah Monyer⁶  Johannes Pfeil⁷  Mirko Pham⁷  Martin Bendszus⁷  Felix Sahm⁸ 

[1] German Cancer Consortium (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany;Center for Childhood and Adolescent Medicine, General Pediatrics, University Hospital, Heidelberg, Heidelberg, Germany;Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany;Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany;Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany;Division of Experimental Radiology, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany;German Centre for Infection Research (DZIF), Heidelberg, Germany

关键词: Cerebral malaria;    Neuroblasts;    Edema;    Magnetic resonance imaging;    Microglial cells;    Inflammation;    Brainstem;    Brain diseases;   

DOI  :  10.1371/journal.ppat.1005470

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY