Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier.
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, whic...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-12-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC4256476?pdf=render |
| _version_ | 1819037690781237248 |
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| author | Adéla Nacer Alexandru Movila Fabien Sohet Natasha M Girgis Uma Mahesh Gundra P'ng Loke Richard Daneman Ute Frevert |
| author_facet | Adéla Nacer Alexandru Movila Fabien Sohet Natasha M Girgis Uma Mahesh Gundra P'ng Loke Richard Daneman Ute Frevert |
| author_sort | Adéla Nacer |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-21T08:25:26Z |
| format | Article |
| id | doaj.art-9495ebb347c64c379ac2f0f8a8cc99df |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-21T08:25:26Z |
| publishDate | 2014-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-9495ebb347c64c379ac2f0f8a8cc99df2022-12-21T19:10:20ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-12-011012e100452810.1371/journal.ppat.1004528Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier.Adéla NacerAlexandru MovilaFabien SohetNatasha M GirgisUma Mahesh GundraP'ng LokeRichard DanemanUte FrevertCerebral 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.http://europepmc.org/articles/PMC4256476?pdf=render |
| spellingShingle | Adéla Nacer Alexandru Movila Fabien Sohet Natasha M Girgis Uma Mahesh Gundra P'ng Loke Richard Daneman Ute Frevert Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier. PLoS Pathogens |
| title | Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier. |
| title_full | Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier. |
| title_fullStr | Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier. |
| title_full_unstemmed | Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier. |
| title_short | Experimental cerebral malaria pathogenesis--hemodynamics at the blood brain barrier. |
| title_sort | experimental cerebral malaria pathogenesis hemodynamics at the blood brain barrier |
| url | http://europepmc.org/articles/PMC4256476?pdf=render |
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