Peptide-Specific Engagement of Cerebrovascular Endothelial Cells Promotes Dysfunctional Calcium Signaling During Experimental Cerebral Malaria

Authors

• M Manglani
• AB Silva
• T Lodhi
• DB McGavern

Abstract

Cerebral malaria is a potentially fatal complication associated with Plasmodium falciparum infection. Disease pathology includes blood brain barrier (BBB) breakdown, microvascular hemorrhage, edema and brainstem herniation. Studies in rodents (referred to as experimental cerebral malaria) have revealed that parasite-specific CD8+ T cells induce this pathology via engagement of cerebrovascular endothelial cells (ECs). In this study, we sought novel insights into the mechanisms underlying alterations in BBB structure and function during the development of ECM. We developed a novel transgenic reporter system that allowed us to simultaneously monitor calcium signaling in cerebrovascular ECs and parasite-specific CD8+ T cells. We then used intravital two-photon microscopy (TPM) to monitor BBB dynamics in real-time at the peak of disease. Within venous networks, we observed a significant increase in the magnitude and propagation of EC calcium signaling. Calcium wave propagation along lengthy stretches of cerebrovascular endothelium was associated with regions of parasite-specific CD8+ T cell engagement (both stable and dynamic). Recognition of cognate peptide-MHC on luminal and abluminal EC surfaces resulted in calcium fluxes within parasite-specific CD8+ T cells, which was followed temporally by calcium wave propagation in the associated vasculature. Importantly, this pathophysiological response was completely eliminated by depletion of T cells. We postulate that T cell-mediated induction of calcium waves along cerebral blood vessels promotes noncytopathic disruption of the BBB. Therapeutic manipulation of this activity might help restore BBB homeostasis and prevent neurological complications during ECM.

Scientific Focus Area: Microbiology and Infectious Diseases

This page was last updated on Friday, March 26, 2021