Initiation of CD8 T cell-mediated blood-brain barrier disruption and neuronal involvement in experimental cerebral malaria

Plasmodium falciparum, deemed “deadliest parasite in humans” by World Health Organization (WHO), results in half a million deaths per year1-3 . Cerebral malaria (CM) is a severe neurological complication of infection with high mortality rate and survivors are often left with severe neurological deficits 2,3 . Due to lack of mechanistic insight into pathogenicity and host immune interactions, therapeutic strategies have been largely ineffective, resulting in parasite resistance and low vaccine efficacy1,4-7 . In order to improve patient outcomes we must address this gap in knowledge and the need to further define the etiology of CM. Plasmodium berghei ANKA (PbA) is an established murine experimental cerebral malaria (ECM) model that closely recapitulates the human disease8-10 . Using our model we were able to show that the cytotoxic function of CD8 T cells is required to induce BBB permeability and ECM, but is not required for CD8 T cell infiltration11 . This demonstration for the requirement of CD8 T cell priming and activation compelled us to analyze the priming event. In our recent work we have shown that mice lacking major histocompatibility complex (MHC) class I on dendritic cells (DC(s)) are unable to initiate the T cell response and show a complete rescue of BBB disruption and are protected from ECM12 . Importantly, the DC subset required to activate the CD8 T cell-mediated BBB disruption in CM has not yet been identified. Identifying this DC could provide a target for immunotherapies and provide the information necessary to further vaccine developments which have halted due to lack of mechanistic insight.

Recent MRI studies have rigorously characterized biomarkers of disease severity in CM2 . Pathological findings include vascular endothelial growth factor (VEGF) upregulation and disruption of BBB tight junctions leading to vascular permeability, severe edema and microhemorrhage2,3,13,14 . VEGF increases seen during neurological disease have been implicated in both pathogenic and neuroprotective roles14-21 . Our lab was the first to demonstrate that neurons were the primary cell type responsible for VEGF increase at a transcriptional level, and that these areas of increase anatomically coincided with vascular permeability during ECM; as shown by MRI. This work was recently presented at the American Association of Immunologists (AAI) Annual Meeting22 . We also have new data demonstrating that cytotoxic CD8 T cell infiltration is required to elicit VEGF upregulation in neurons. However, whether neuronal-VEGF promotes BBB permeability or is a consequence of it is unknown.

NIH Reporter - Project details

Basic Science

Aug 2020 — Jul 2022

$91,040

United States