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Early synergy between IFNγ-inducible Gbp4 and Irgb6 in the olfactory bulb contributes to experimental cerebral malaria pathology

ABSTRACT: Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection. Although much progress has been made in understanding CM, the precise pathogenesis remains elusive. The olfactory bulb (OB) has emerged as a critical site of immunopathology in experimental cerebral malaria (ECM) models, but its contribution to disease progression is not fully understood. To investigate the molecular mechanisms driving early ECM pathogenesis, we conducted transcriptomic profiling of the OB to identify key gene signatures associated with disease onset. Our analysis revealed significant early upregulation of IFN-inducible GTPases, particularly Irgb6 and Gbp4, effectors downstream of IFN-γ, but not IFN-α/β signalling, suggesting their involvement in ECM pathology. Using Gbp4-/-, Irgb6-/-, and double knockout (Irgb6-/- Gbp4-/-) mice, we identified a synergistic pathological role for these GTPases. Mechanistically, we found that double-knockout mice exhibited increased infiltration of CD4+ and CD8+ T cells into the brain but with reduced T cell functionality and impaired antigen presentation by endothelial cells, leading to enhanced parasite accumulation in the OB. This disruption in immune regulation ultimately conferred improved survival in the Irgb6-/- Gbp4-/- mice and indicated the pathological impact of Gbp4 and Irgb6 in ECM. These findings reveal that Gbp4 and Irgb6 synergistically play crucial roles in the early immunopathogenesis of ECM by modulating antigen processing and presentation in the OB, thereby shaping immune cell dynamics. Our work shows the dual role of Irgb6 and Gbp4 GTPases in host defence and immunopathology and offers new insights into ECM mechanisms and potential therapeutic targets for CM intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE282591 | GEO | 2025/07/01

REPOSITORIES: GEO

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Project 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.

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Early synergy between IFNγ-inducible Gbp4 and Irgb6 in the olfactory bulb contributes to experimental cerebral malaria pathology

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