Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria
Abstract Sequestration of infected red blood cells (iRBCs) in the microcirculation is a hallmark of cerebral malaria (CM) in post-mortem human brains. It remains controversial how this might be linked to the different disease manifestations, in particular brain swelling leading to brain herniation a...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46617-w |
| _version_ | 1797259186938052608 |
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| author | A. M. Oelschlegel R. Bhattacharjee P. Wenk K. Harit H-J Rothkötter S. P. Koch P. Boehm-Sturm K. Matuschewski E. Budinger D. Schlüter J. Goldschmidt G. Nishanth |
| author_facet | A. M. Oelschlegel R. Bhattacharjee P. Wenk K. Harit H-J Rothkötter S. P. Koch P. Boehm-Sturm K. Matuschewski E. Budinger D. Schlüter J. Goldschmidt G. Nishanth |
| author_sort | A. M. Oelschlegel |
| collection | DOAJ |
| description | Abstract Sequestration of infected red blood cells (iRBCs) in the microcirculation is a hallmark of cerebral malaria (CM) in post-mortem human brains. It remains controversial how this might be linked to the different disease manifestations, in particular brain swelling leading to brain herniation and death. The main hypotheses focus on iRBC-triggered inflammation and mechanical obstruction of blood flow. Here, we test these hypotheses using murine models of experimental CM (ECM), SPECT-imaging of radiolabeled iRBCs and cerebral perfusion, MR-angiography, q-PCR, and immunohistochemistry. We show that iRBC accumulation and reduced flow precede inflammation. Unexpectedly, we find that iRBCs accumulate not only in the microcirculation but also in large draining veins and sinuses, particularly at the rostral confluence. We identify two parallel venous streams from the superior sagittal sinus that open into the rostral rhinal veins and are partially connected to infected skull bone marrow. The flow in these vessels is reduced early, and the spatial patterns of pathology correspond to venous drainage territories. Our data suggest that venous efflux reductions downstream of the microcirculation are causally linked to ECM pathology, and that the different spatiotemporal patterns of edema development in mice and humans could be related to anatomical differences in venous anatomy. |
| first_indexed | 2024-04-24T23:05:26Z |
| format | Article |
| id | doaj.art-eb09a5a743bd4f8186010514f8bfe340 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T23:05:26Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-eb09a5a743bd4f8186010514f8bfe3402024-03-17T12:32:20ZengNature PortfolioNature Communications2041-17232024-03-0115111810.1038/s41467-024-46617-wBeyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malariaA. M. Oelschlegel0R. Bhattacharjee1P. Wenk2K. Harit3H-J Rothkötter4S. P. Koch5P. Boehm-Sturm6K. Matuschewski7E. Budinger8D. Schlüter9J. Goldschmidt10G. Nishanth11Combinatorial NeuroImaging Core Facility, Leibniz Institute for NeurobiologyCombinatorial NeuroImaging Core Facility, Leibniz Institute for NeurobiologyCombinatorial NeuroImaging Core Facility, Leibniz Institute for NeurobiologyInstitute of Medical Microbiology and Hospital Epidemiology, Hannover Medical SchoolInstitute of Anatomy, Medical Faculty, Otto-von-Guericke-University MagdeburgCharité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Experimental Neurology and Center for Stroke Research, Charitéplatz 1Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Experimental Neurology and Center for Stroke Research, Charitéplatz 1Department of Molecular Parasitology, Institute of Biology, Humboldt UniversityCombinatorial NeuroImaging Core Facility, Leibniz Institute for NeurobiologyInstitute of Medical Microbiology and Hospital Epidemiology, Hannover Medical SchoolCombinatorial NeuroImaging Core Facility, Leibniz Institute for NeurobiologyInstitute of Medical Microbiology and Hospital Epidemiology, Hannover Medical SchoolAbstract Sequestration of infected red blood cells (iRBCs) in the microcirculation is a hallmark of cerebral malaria (CM) in post-mortem human brains. It remains controversial how this might be linked to the different disease manifestations, in particular brain swelling leading to brain herniation and death. The main hypotheses focus on iRBC-triggered inflammation and mechanical obstruction of blood flow. Here, we test these hypotheses using murine models of experimental CM (ECM), SPECT-imaging of radiolabeled iRBCs and cerebral perfusion, MR-angiography, q-PCR, and immunohistochemistry. We show that iRBC accumulation and reduced flow precede inflammation. Unexpectedly, we find that iRBCs accumulate not only in the microcirculation but also in large draining veins and sinuses, particularly at the rostral confluence. We identify two parallel venous streams from the superior sagittal sinus that open into the rostral rhinal veins and are partially connected to infected skull bone marrow. The flow in these vessels is reduced early, and the spatial patterns of pathology correspond to venous drainage territories. Our data suggest that venous efflux reductions downstream of the microcirculation are causally linked to ECM pathology, and that the different spatiotemporal patterns of edema development in mice and humans could be related to anatomical differences in venous anatomy.https://doi.org/10.1038/s41467-024-46617-w |
| spellingShingle | A. M. Oelschlegel R. Bhattacharjee P. Wenk K. Harit H-J Rothkötter S. P. Koch P. Boehm-Sturm K. Matuschewski E. Budinger D. Schlüter J. Goldschmidt G. Nishanth Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria Nature Communications |
| title | Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria |
| title_full | Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria |
| title_fullStr | Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria |
| title_full_unstemmed | Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria |
| title_short | Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria |
| title_sort | beyond the microcirculation sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria |
| url | https://doi.org/10.1038/s41467-024-46617-w |
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