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

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.