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Initiation of CD8 T cell-mediated BBB disruption and neuronal involvement in experimental cerebral malaria

实验性脑型疟疾中 CD8 T 细胞介导的 BBB 破坏和神经元受累的启动

基本信息

批准号：
10219208
负责人：
Cori Elizabeth Fain
金额：
$ 4.6万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219208
关键词：
Address Adoptive Transfer American Anatomy Animals Antigen-Presenting Cells Area Biological Markers Blood - brain barrier anatomy Brain C57BL/6 Mouse CD8-Positive T-Lymphocytes Cells Cerebral Malaria Cessation of life Clinical Cognitive deficits Complication Data Dendritic Cells Development Diagnosis Disease Disease Progression Drug resistance Edema Etiology Event Feedback Future Genetic Transcription Human Immune Immune system Immunologist Immunotherapy In Situ Hybridization Infection Knock-out Knockout Mice Knowledge Lead Left Leukocytes Magnetic Resonance Imaging Major Histocompatibility Complex Malaria Mediating Methods Modeling Mus Neurologic Neurons Outcome Parasite resistance Parasites Pathogenesis Pathogenicity Pathologic Pathology Patient-Focused Outcomes Permeability Plasmodium berghei Plasmodium falciparum Proteins RNA Research Role Severities Severity of illness Survivors T cell response Testing Therapeutic Therapeutic Intervention Tight Junctions Time Tissues Transgenic Mice Tumor-infiltrating immune cells Up-Regulation Vaccines Vascular Endothelial Growth Factors Vascular Permeabilities Work World Health Organization blood-brain barrier disruption blood-brain barrier permeabilization cell type conditional knockout cytotoxic cytotoxic CD8 T cells defined contribution field study improved in vivo innovation insight knockout animal malaria infection mortality mouse model nervous system disorder novel novel imaging technique novel therapeutics targeted treatment therapeutic target transcription factor vaccine development

项目摘要

Project Summary/Abstract: Plasmodium falciparum, deemed “deadliest parasite in humans” by World Health Organization is the causative agent of the disease known as malaria. Malaria infections result in approximately half a million deaths per year. Cerebral malaria (CM) is a deadly neurological complication of Plasmodium falciparum infection resulting in high mortality or severe cognitive deficit. Drug resistance, low efficacy of new therapeutics, and unknown mechanism of pathology and host immune interactions highlight the urgent need to develop solutions for this tremendous global issue. Work from our lab and others have shown that leukocyte accumulation in the brain is correlated with CM onset and severity, establishing a vital role of the immune system in pathology. The roles of some immune cell subsets are well-established such as that of CD8 T cells which have been shown to mediate blood-brain barrier disruption and vascular permeability in the late stages of infection. However, the role of the antigen-presenting cell (APC) that initiates this CD8 T cell response remains elusive. Our lab will employ novel cell-type specific deletion of the two MHC class I molecules found in C57BL/6 mice (H-2Kb and H-2Db) in order identify this cell type. Mice deficient in either class I molecule on dendritic cells ((DC)s) are protected from cerebral malaria. Therefore, in this proposal we plan to adoptively transfer in class I sufficient, pre-sorted DCs of established subsets to identify the DC capable of initiating the CD8 T cell responses and blood-brain barrier (BBB) disruption seen in CM. Identifying and characterizing this cell type will have broad implications in the field ranging from fundamental insights into pathogenesis as well as improvement of vaccine strategies. After addressing the initiating event we will characterize the pathologic outcome. CM is clinically characterized by VEGF upregulation in the brain, and disruption of BBB tight junction proteins, vascular permeability, and severe edema detectable by MRI. In our studies we employ small animal MRI and RNA in situ hybridization to diagnose the presence of these biomarkers. We recently demonstrated that neurons are the cell type responsible for VEGF transcriptional upregulation in the disease state. To address the role of VEGF in either supporting or negating pathology we generated a new inducible mouse line capable of knocking out VEGF specifically in neurons. After establishing infection we can induce knockout of neuronal-VEGF and assess pathology. Elaborating upon the role of VEGF in CM will have therapeutic implications as well as provide insight into methods of disease progression. Completion of these aims will allow us to address our central hypothesis that a specific DC subset is required to elicit cytotoxic effector CD8 T cell-mediated BBB permeability and neuronal VEGF upregulation; which reinforces pathology in ECM. These findings will prove novel in any capacity and will contribute fundamental knowledge to several fields of study, provide mechanistic insight into pathogenesis of malaria and determine potential targets of therapeutic intervention for the future.

项目总结/文摘: