Brain Endothelial Cells Exposure to Malaria Parasites Links Type I Interferon Signalling to Antigen Presentation, Immunoproteasome Activation, Endothelium Disruption, and Cellular Metabolism

Abstract

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 I 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 I IFN signaling and immunoproteasome activation are also involved in the dysfunction of the endothelial barrier through disturbing gene expression in the Wnt/{beta}-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/{beta}-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 amino acid catabolites. In accordance, glycolysis blockade in vivo delayed the clinical onset of CM in mice. Our results unveiled that Type I 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 I IFN signaling and its downstream effects are licensed by dramatic increase in glucose uptake impacting on energy metabolism pathways. This work substantiates the hypothesis that Type I IFN-immunoproteasome induction response in BECs contributes to CM pathology and fatality (1) by increasing antigen presentation to cytotoxic CD8+ T cells and (2) by promoting endothelial barrier dysfunction, favoring brain vasogenic edema. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/518027v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@859960org.highwire.dtl.DTLVardef@1186de4org.highwire.dtl.DTLVardef@d6b625org.highwire.dtl.DTLVardef@50751d_HPS_FORMAT_FIGEXP M_FIG C_FIG AUTHOR SUMMARYCerebral malaria is a severe clinical form of malaria infection that leads to respiratory arrest and death due to brain swelling. Disruption of blood vessels in the brain barrier is a hallmark of cerebral malaria development. However, the underlying pathological mechanisms are still unsettled. We explored the hypothesis that immune response of brain blood vessels to malaria infection is an initiator of inflammatory events leading to cerebral malaria. Our experiments unveiled that proinflammatory Type I interferon action increases the presentation of parasite molecules by brain blood vessel cells to cytotoxic immune cells and promotes brain vessel disruption. We found that these effects are determined by activation of protein degradation systems upon exposure of brain blood vessel cells to malaria parasite-infected erythrocytes. Our findings unveil a critical role of Type I interferon in brain blood vessels cells signaling in initiating immunopathology mechanisms associated to cerebral malaria development and suggest that blocking Type I interferon induction in the brain provides a path to prevent this disease.