NK cell depletion promotes maintenance of blood-brain barrier integrity and survival following lethal infection with Venezuelan equine encephalitis virus.

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Presentation Time: 10:30 AM - 10:45 AM
Abstract ID: 5216 - B

Presenting Author:
Margarita V Rangel , Postdoc at Lawrence Livermore Natl. Lab.

Abstract:

Venezuelan equine encephalitis virus (VEEV) is a weaponizable pathogen of humans and livestock for which there are no licensed vaccines or therapeutics. The host immune response in the brain has been implicated as having immunopathological effects yet the underlying mechanisms and specific immune cell populations involved have not been elucidated. We are investigating the neuroinflammatory response that occurs during VEEV infection that leads to pathological outcomes such as blood-brain barrier (BBB) disruption. We applied single-cell RNA sequencing to immune cells isolated from infected mouse brains to generate a high-resolution profile of sequential changes in gene expression. In probing the effects of specific immune cell populations, we found that natural killer (NK) cells significantly contribute to the loss of BBB integrity. We show that depletion of NK cells prior to infection decreases BBB permeability, protects against neurological symptoms, and promotes survival. Our ongoing analysis and future work will further define the underlying mechanisms that contribute to BBB dysfunction and neurological disease, including the steps and molecular players of NK cell recruitment and cytotoxic activity. This work contributes to our understanding of how VEEV causes disease and highlights the potential for host-based immune-modulatory therapeutic targets for VEEV, infections with other encephalitic pathogens, and potentially against non-infectious neuroinflammatory conditions.