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Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
Blood-brain barrier breakdown during cerebral malaria: suicide or murder?
Paco Pino1, Zacharie Taoufiq, Josiane Nitcheu
1INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Paris, France.
Abstract:
Cerebral malaria, one of the most serious complications of Plasmodium falciparum infection, is characterized by the sequestration of parasitized red blood cells (PRBCs) in cerebral microvascular beds. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances, and host immune responses all play a role. Sequestration of PRBCs is mediated by different endothelial cell surface receptors, mainly ICAM-1 and CD36. In vitro studies demonstrated that PRBC adhesion to endothelial cells induces over-expression of various adhesion molecules including ICAM-1, expression of iNOS, oxidative stress and finally apoptosis in endothelial cells. In vivo studies, in humans and in mice models of cerebral malaria brought striking evidence of the implication of brain infiltrating cytotoxic effector CD8T lymphocytes in the development of murine cerebral malaria pathogenesis. These cells probably act by direct cytotoxicity against endothelial cells. Cytotoxicity and apoptosis potentially lead blood-brain-barrier disruption and could contribute to the development of cerebral malaria. We propose a key role for endothelial cells in the pathogenesis of cerebral malaria, both by suicide / apoptosis, and / or by murder / cytotoxicity.
Insights
Cerebral malaria pathogenesis involves parasite sequestration and immune responses. Endothelial cells play a key role through apoptosis and cytotoxicity, potentially disrupting the blood-brain barrier.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- Cerebral malaria, a severe Plasmodium falciparum complication, involves parasitized red blood cell sequestration in brain vessels.
- Neuropathology mechanisms are unclear, but parasite sequestration, metabolic issues, and immune responses are implicated.
- Parasite-infected red blood cell sequestration utilizes endothelial receptors like ICAM-1 and CD36.
Purpose of the Study:
- To investigate the role of endothelial cells in cerebral malaria pathogenesis.
- To explore mechanisms of endothelial cell damage, including apoptosis and cytotoxicity.
Main Methods:
- In vitro studies on endothelial cell responses to parasitized red blood cell adhesion.
- In vivo studies using human and murine models of cerebral malaria.
- Analysis of endothelial cell surface receptor expression, iNOS, oxidative stress, and apoptosis.
Main Results:
- Parasitized red blood cell adhesion induces endothelial cell overexpression of ICAM-1, iNOS, oxidative stress, and apoptosis in vitro.
- In vivo studies highlight the role of cytotoxic CD8T lymphocytes in cerebral malaria pathogenesis.
- Endothelial cell damage via apoptosis and cytotoxicity contributes to blood-brain barrier disruption.
Conclusions:
- Endothelial cells are central to cerebral malaria pathogenesis.
- Both endothelial cell self-destruction (apoptosis) and immune cell-mediated damage (cytotoxicity) contribute to disease progression.
- Understanding these mechanisms is crucial for developing therapeutic strategies against cerebral malaria.
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