# Modulation of Blood-Brain Barrier Defense and Dysfunction during Bacterial Meningitis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $30,209

## Abstract

PROJECT SUMMARY
Bacterial meningitis is the most common serious infection of the central nervous system (CNS) and a major
cause of death and disability worldwide, especially in children. Although antibiotic therapy has changed
bacterial meningitis from a uniformly fatal disease to an often curable one, the overall outcome remains
unfavorable, with mortality of 5 to 10% and permanent neurologic sequelae occurring in 5 to 40% of survivors,
depending on patient age and pathogen. Disruption and dysfunction of the blood-brain barrier (BBB) is a
hallmark event in the pathophysiology of bacterial meningitis. Little is known, however, about the very first and
crucial interaction between a bacterial pathogen with the BBB that initiates this chain of events, and may
ultimately determine a poor or favorable neurological outcome in meningitis patients. This proposal seeks to
elucidate the molecular mechanisms of BBB disruption during bacterial infection, and why it fails as a
neuroprotective barrier during bacterial meningitis. We have shown that bacterial infection induces an epithelial
to mesenchymal transition (EMT) program in endothelial cells (EndoMT), disrupting tight junctions in BBB
endothelium through the upregulation of host transcription factor Snail1, a global repressor of tight junctions.
Further, we have discovered that a bacterial adhesin interacts directly with vimentin, an intermediate filament
protein that is induced during EMT/EndoMT. I hypothesize that BBB disruption may be due to the combined
effect of bacterial entry and modulation of host signaling pathways that results in compromised barrier function.
Further that bacterial pathogens associated with CNS disease possess the unique ability to penetrate brain
endothelium, which ultimately leads to BBB dysfunction. These hypotheses will be addressed with both in vitro
and in vivo models of BBB penetration using Group B streptococcus (GBS) as a model human pathogen
associated with meningitis. AIM 1: Characterize the bacterial determinant(s) that initiate Snail1 activation and
the contribution of Snail1 to BBB breakdown during GBS meningitis; AIM 2: Characterize the host factors that
contribute to Snail1 activation during GBS infection; AIM 3: Determine the contribution of GBS-vimentin
interaction to BBB penetration and the development of meningitis. These studies should increase our
understanding of the bacterial and host factors involved in the interaction with brain endothelium that leads to
barrier disruption, pathogen transit into the brain, and disease progression.

## Key facts

- **NIH application ID:** 10137702
- **Project number:** 3R01NS116716-01A1S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kelly S Doran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,209
- **Award type:** 3
- **Project period:** 2020-02-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137702

## Citation

> US National Institutes of Health, RePORTER application 10137702, Modulation of Blood-Brain Barrier Defense and Dysfunction during Bacterial Meningitis (3R01NS116716-01A1S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137702. Licensed CC0.

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