Olfactory Plays a Key Role in Spatiotemporal Pathogenesis of Cerebral Malaria

•Ultra-high-field MRI imaging identifies a vulnerable spot in brain during ECM•Intravital imaging shows Plasmodium parasites adhere in the olfactory bulb•High fever and olfaction loss associate with brain dysfunction during ECM•OLF astrocytes and CCL21 may regulate CD11c+ CD8 T cell entry via CXCR3

SummaryCerebral malaria is a complication of Plasmodium falciparum infection characterized by sudden coma, death, or neurodisability. Studies using a mouse model of experimental cerebral malaria (ECM) have indicated that blood-brain barrier disruption and CD8 T cell recruitment contribute to disease, but the spatiotemporal mechanisms are poorly understood. We show by ultra-high-field MRI and multiphoton microscopy that the olfactory bulb is physically and functionally damaged (loss of smell) by Plasmodium parasites during ECM. The trabecular small capillaries comprising the olfactory bulb show parasite accumulation and cell occlusion followed by microbleeding, events associated with high fever and cytokine storm. Specifically, the olfactory upregulates chemokine CCL21, and loss or functional blockade of its receptors CCR7 and CXCR3 results in decreased CD8 T cell activation and recruitment, respectively, as well as prolonged survival. Thus, early detection of olfaction loss and blockade of pathological cell recruitment may offer potential therapeutic strategies for ECM.

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