# Mechanistic Study of Stroke-induced Immune Suppression and Identification of Immune Modulatory Targets for Stroke-associated Pneumonia

> **NIH NIH P20** · WEST VIRGINIA UNIVERSITY · 2021 · $299,918

## Abstract

Project Summary/Abstract
Stroke-associated pneumonia (SAP) is the major cause of mortality in patients who have suffered from acute
ischemic stroke. Multi-center clinical studies suggested that prophylactic antibiotic treatments do not reduce
the incidence of mortality or SAP. Moreover, the emergence of antibiotic resistant bacteria renders the “gold
standard” antibiotic treatments ineffective. Therefore, novel therapeutic strategies are needed to improve
clinical outcomes. Studies utilizing animal models of focal brain ischemia demonstrated that stroke-induced
immune suppression is one of the causes of SAP. The overall goal of this proposal is to understand the cause
of stroke-induced immune suppression and identify novel therapeutic targets for SAP. Innate immune cells
including neutrophils, monocytes, macrophages, and dendritic cells (DCs) are the first line of lung immune
defense, which is followed by subsequent recruitment and activation of the antigen-specific T and B cells. In
phase one of the Stroke CoBRE, we used transient middle cerebral artery occlusion (tMCAO), a mouse model
of focal brain ischemia, to analyze immune cell niches in the brain and the lungs, as well as determined the
expression of inflammatory cytokines and chemokines in the lungs after ischemic stroke induction. Our
preliminarily data demonstrate that 1) ischemic stroke increases the number of alveolar macrophages, CD11b+
DCs, and neutrophils in the lungs, but monocyte number remains unchanged despite an increased expression
of monocyte chemoattractant CCL2; 2) monocyte number is significantly increased in the brain after ischemic
stroke induction; 3) ischemic stroke decreases the number of T cells, B cells, and NK cells in the lungs,
correlating with the reduction of chemokines CCL5 and CCL22. These observations suggest that ischemic
stroke events alter the immune cell niches in the lungs and potentially impair their functions.
 Using tMCAO coupled with P. aeruginosa infection, we propose to further test our hypothesis that SAP
is caused by the impairment of the lung-specific, anti-bacterial innate immunity. Our hypothesis will be tested in
three aims. In Aim 1, we will determine the phagocytic and bactericidal activities of innate immune cells in the
lungs following tMCAO and P. aeruginosa infection. In Aim 2, we will test our hypothesis that monocyte
infiltration to the brain after ischemic stroke impedes their infiltrating to the lungs, and thereby contributes to
SAP. We will test this hypothesis by adoptive transfer of purified monocytes from B6 CD45.2 mice to the B6
CD45.1 congenic strain recipient mice, followed by tMCAO and P. aeruginosa infection. In Aim 3, we will
investigate the protective role of CCL5 and CCL22 in SAP by determining if intratracheal administration of
these chemokines restores lymphocyte availability and reduces severity of SAP. We are hopeful that this
research will identify key immune cell types, molecular pathways, and downstream mediator...

## Key facts

- **NIH application ID:** 10217167
- **Project number:** 5P20GM109098-07
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** EDWIN CHI KEUNG WAN
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $299,918
- **Award type:** 5
- **Project period:** 2014-09-08 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217167

## Citation

> US National Institutes of Health, RePORTER application 10217167, Mechanistic Study of Stroke-induced Immune Suppression and Identification of Immune Modulatory Targets for Stroke-associated Pneumonia (5P20GM109098-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10217167. Licensed CC0.

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