PXD039805

PXD039805 is an original dataset announced via ProteomeXchange.

Title	Brain Endothelial Cells Exposure to Malaria Parasites Links Type I Interferon Signalling to Antigen Presentation, Immunoproteasome Activation Endothelium Disruption, and Cellular Metabolism
Description	Cerebral malaria (CM) lethality is attributable to brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored. Activation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the innate immune response in cerebral malaria (CM) development in mouse models. Using a T cell-reporter system, we show that Type 1 IFN signaling in BECs exposed to Plasmodium berghei-infected erythrocytes (PbA-IE), functionally enhances MHC Class-I antigen presentation through gamma-interferon independent immunoproteasome activation and impacted the proteome functionally related to vesicle trafficking, protein processing, and folding and antigen presentation. In vitro assays show that Type 1 IFN signaling and immunoproteasome activation are also involved in the dysfunction of the endothelial barrier through disturbing gene expression in the Wnt/ß-catenin signaling pathway. We demonstrate that IE exposure induces a substantial increase in BECs glucose uptake while glycolysis blockade abrogates INFb secretion impairing immunoproteasome activation, antigen presentation, and Wnt/ ß-catenin signaling. Metabolome analysis show that energy demand and production are markedly increased in BECs exposed to IE as revealed by enriched content in glucose and fatty acid catabolites. In accordance, glycolysis blockade in vivo delayed the clinical onset of CM in mice. Our results unveiled that Type 1 IFN signaling and subsequent immunoproteasome activation in BECs contribute to enhanced antigen presentation and the impairment of the endothelial barrier function. We also show that Type 1 IFN signaling and its downstream effects are licensed by dramatic increase in glucose uptake with an impact on energy metabolism pathways. This work raises the hypothesis that Type 1 IFN- immunoproteasome induction response in BECs contributes to CM pathology and fatality (1) by increasing antigen presentation to cytotoxic CD8+ T cells, which is a determinant of brain cytotoxic edema and (2) by promoting endothelial barrier dysfunction, that likely favors brain vasogenic edema.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:00:35.610.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Akos Vegvari
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-02 08:31:50	ID requested
1	2023-03-13 08:30:32	announced
⏵ 2	2023-11-14 09:00:36	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: Cerebral malaria, Type I interferon, endotherial cells, Wnt/beta-catenin signaling

Akos Vegvari
contact affiliation	Proteomics Biomedicum, Karolinska Institutet, Stockholm, Sweden
contact email	akos.vegvari@ki.se
lab head
Akos Vegvari
contact affiliation	Karolinska Institutet
contact email	akos.vegvari@ki.se
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD039805

PRIDE project URI

• PRIDE
  1. PXD039805
     1. Label: PRIDE project
     2. Name: Brain Endothelial Cells Exposure to Malaria Parasites Links Type I Interferon Signalling to Antigen Presentation, Immunoproteasome Activation Endothelium Disruption, and Cellular Metabolism