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CD8(+) T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature
- Source :
- PLoS Pathogens, Vol 12, Iss 12, p e1006022 (2016), PLoS Pathogens, 12(12), PLoS Pathogens
- Publication Year :
- 2016
-
Abstract
- Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-γ, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen-dependent interactions with cerebrovasculature.<br />Author Summary Cerebral malaria (CM) is a severe and potentially fatal complication of malaria in humans that results in swelling and bleeding within the brain. The mechanisms that cause this fatal disease in humans are not completely understood. We studied an animal model known as experimental cerebral malaria to learn more about the factors that drive this disease process. Using a technique referred to as intravital microscopy, we captured movies of immune cells operating in the living brain as the disease developed. At the peak of disease, we observed evidence of immune cells interacting with and aggregating along blood vessels throughout the brain. These interactions were directly associated vascular leakage. This caused the brain to swell, which gave rise to an unsustainable pressure that ultimately killed neurons responsible for heart and lung function. The fatal swelling was induced by immune cells (referred to as T cells) interacting with bits of parasite presented by blood vessels in the brain. Removal of this parasite presentation protected the mice from fatal disease. We also evaluated a straightforward therapy that involved intravenous administration of antibodies that interfered with T cell sticking to blood vessels. Our movies revealed that this therapeutic approach rapidly displaced T cells from the blood vessels in the brain and prevented fatal disease.
- Subjects :
- Central Nervous System
0301 basic medicine
Pathology
Plasmodium berghei
CD8-Positive T-Lymphocytes
Nervous System
Pathogenesis
Mice
White Blood Cells
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
Cytotoxic T cell
Biology (General)
Neuronal Death
Cell Death
biology
T Cells
Brain
Flow Cytometry
Immunohistochemistry
medicine.anatomical_structure
Blood-Brain Barrier
Cell Processes
Cerebral Malaria
Cellular Types
Anatomy
Brainstem
Research Article
Programmed cell death
medicine.medical_specialty
QH301-705.5
Immune Cells
T cell
Immunology
Malaria, Cerebral
Mice, Transgenic
Cytotoxic T cells
Microbiology
03 medical and health sciences
Antigen
Virology
MHC class I
Parasitic Diseases
Genetics
medicine
Animals
Molecular Biology
Blood Cells
Biology and Life Sciences
Cell Biology
RC581-607
Tropical Diseases
Malaria
Disease Models, Animal
030104 developmental biology
Cardiovascular Anatomy
biology.protein
Blood Vessels
Parasitology
Immunologic diseases. Allergy
CD8
Brain Stem
030215 immunology
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens, Vol 12, Iss 12, p e1006022 (2016), PLoS Pathogens, 12(12), PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....59fa40b5dd923d351d74092d62d7bd73