# Bacterial disruption of neuroimmune pathways in a transparent brain

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $1,422,000

## Abstract

Project Summary/Abstract
 Cells of the immune system, bacteria, and neurons are constantly interacting on every
surface of the human body. Recent studies show that bacteria have evolved mechanisms to
engage with the nervous system, often using the phagocytes that regulate inflammation.
Neuroinflammation, or inflammation in neurological tissue, is thought to contribute to common
neurodegenerative conditions, including Alzheimer's disease and Parkinson's disease, although
the basic mechanisms of neuroinflammation remain incompletely understood. The long-term
objective of this New Innovator Award proposal is to define the molecular mechanisms of
neuroinflammation during infection. The innovation is our adaptation of the cutting-edge
zebrafish molecular toolkit (optogenetics, biosensors, in vivo biotinylation) to host-pathogen
interactions. With this system, we can genetically modify host and pathogen, then observe
bacteria invading the transparent zebrafish brain in real-time. As pathogens, we use
mycobacterial species that activate neuroinflammation in humans (TB meningitis, leprosy) and
in zebrafish. We have also developed new zebrafish brain infection models, using human
pathogens isolated from meningitis patients, in order to determine:
Project 1: How do bacteria invade the brain from the blood?
 Approach: Define the endothelial mechanisms of brain invasion and vascular injury.
Project 2: How do host versus pathogen factors drive catastrophic brain inflammation?
 Approach: Optogenetic (light-activated) control of phagocytes in vivo.
Project 3: How do host versus pathogen factors injure neurons?
 Approach: Identifying infectious mechanisms of neuronal injury using biosensors.
 To answer these questions, this proposal combines immunobiology and neurobiology
tools with brain infection models in zebrafish. Using live imaging of zebrafish brain infection,
and genetic modification of fluorescent bacteria, neurons, and phagocytes, the earliest
inflammatory and neurodegenerative events can be directly observed in unprecedented detail.
Completion of this work fulfills two goals. First, it will provide needed mechanistic information
on the host cells and molecules that mediate injury in understudied brain infections that
disproportionately affect people living in poverty. This will support the goal of developing new
therapies that limit brain inflammation. Beyond infection, the basic biological mechanisms of
neuroinflammation, revealed by infection, will likely be relevant to the many non-infectious
neurodegenerative conditions that are characterized by neuroinflammation.

## Key facts

- **NIH application ID:** 10245966
- **Project number:** 1DP2NS127277-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Cressida Arianna Madigan
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,422,000
- **Award type:** 1
- **Project period:** 2021-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245966

## Citation

> US National Institutes of Health, RePORTER application 10245966, Bacterial disruption of neuroimmune pathways in a transparent brain (1DP2NS127277-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245966. Licensed CC0.

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