Journal article
Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria
Brain (London, England : 1878), Vol.147(2), pp.566-589
02/01/2024
DOI: 10.1093/brain/awad319
PMCID: PMC11734323
PMID: 37776513
Abstract
Abstract Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell MHC class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class-I-like molecules which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies we interrogate human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observe that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T cell infiltration, targeted cell death, and regional blood-brain barrier (BBB) disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T cell activation, attenuated T cell interaction with brain vasculature, lessened targeted cell death, preserved BBB integrity, and prevented ECM and the death of the animal. We were able to show that these events were brain specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.
Details
- Title: Subtitle
- Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria
- Creators
- Cori E Fain - Mayo ClinicJiaying Zheng - Mayo ClinicFang Jin - Mayo ClinicKatayoun Ayasoufi - Mayo ClinicYue Wu - Mayo ClinicMeredith T Lilley - Mayo ClinicAbigail R Dropik - Mayo ClinicDelaney M Wolf - Mayo ClinicRobert C Rodriguez - Mayo ClinicAibaidula Abudumijiti - Mayo ClinicZachariah P Tritz - Mayo ClinicSamantha M Bouchal - Mayo ClinicLecia L Pewe - University of IowaStina L Urban - University of IowaYin Chen - Mayo ClinicSu-Youne Chang - Mayo ClinicMichael J Hansen - Mayo ClinicJennifer M Kachergus - Mayo Clinic in FloridaJi Shi - Mayo Clinic in FloridaE Aubrey Thompson - Mayo Clinic in FloridaHadley E JensenJohn T Harty - University of IowaIan F Parney - Mayo ClinicJie Sun - University of VirginiaLong-Jun Wu - Mayo ClinicAaron J Johnson - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.147(2), pp.566-589
- DOI
- 10.1093/brain/awad319
- PMID
- 37776513
- PMCID
- PMC11734323
- NLM abbreviation
- Brain
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Grant note
- DOI: 10.13039/100000871, name: Mayo Clinic; name: Training Grant in Basic Immunology, award: T32 AI07425-24; name: Nanostring-Glial Panel Grant
- Language
- English
- Electronic publication date
- 09/30/2023
- Date published
- 02/01/2024
- Academic Unit
- Pathology
- Record Identifier
- 9984473779202771
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