# Alcohol impairs the HSPC response to septic infection

> **NIH NIH R21** · NORTHEAST OHIO MEDICAL UNIVERSITY · 2024 · $224,250

## Abstract

Project Summary/Abstract
 Alcohol abuse increases the host risk of developing serious infections, particularly septicemia/sepsis.
Neutrophil granulocytes constitute the first line of phagocytic defense against bacterial pathogens. Our recent
studies have demonstrated that activation of hematopoietic stem cells (HSCs) is crucial for enhancing
granulocyte production by bone marrow in response to bacterial infection. Alcohol impairs this critical step of
the granulopoietic response. Currently, knowledge about the underlying mechanisms remains limited.
Guanylate-binding protein 7 (GBP7) is a member of the 65KDa large cytokine inducible GTPase family. Little is
known about the function of GBP7 in hematopoietic stem/progenitor cells (HSPCs). Our pilot studies revealed
that GBP7 expression by HSPCs was markedly upregulated at both mRNA and protein levels in mice with E.
coli septicemia. This increase in GBP7 expression was accompanied by activation of HSPCs. Chronic plus
binge alcohol administration suppressed the upregulation of GBP7 expression along with inhibition of HSPC
activation during E. coli septicemia. Searching promoter regions of murine and human GBP7 genes showed
multiple Fos/Jun binding sites. Alcohol suppressed activation of c-Jun N-terminal kinases (JNK1/2) in marrow
cells during septicemia. Inhibition of JNK1/2 activation with specific inhibitor suppressed lipopolysaccharide-
induced up-regulation of GBP7 expression by HSPCs. The predominant distribution of GBP7 was detected in
nuclei of HSPCs from both murine and human origins. Septic stimuli caused a marked enhancement of GBP7
expression in the nuclei of HSPCs, which implied a close association of GBP7 with the change in nuclear
activity. GBP activation leads to their conformational changes facilitating interaction of these large GTPases
with different macromolecules to form complexes for carrying out different functions in cells. Cyclin D1-cyclin-
dependent kinase (CDK) 4/6 signaling drives HSPC proliferation. Septicemia caused a marked increase in
cyclin D1 expression and enhancement of proliferation in HSPCs, both of which were suppressed by alcohol or
GBP7 knockout (KO). GBP7 KO impaired marrow granulopoietic response, which was similar to what caused
by alcohol intoxication. Our current project proposes to explore the role of GBP7 in the regulation of HSPC
activation and investigate how alcohol impairs it. The central hypothesis is that alcohol inhibits GBP7 signaling
for HSPC activation during the granulopoietic response to septic infection. Two specific aims are: 1) to
examine if alcohol suppresses up-regulation of GBP7 expression by HSPCs via inhibiting activation of the toll-
like receptor (TLR) 4-JNK1/2-Fos/Jun pathway in response to septic infection; 2) to determine if alcohol inhibits
HSPC activation during the granulopoietic response via impairing GBP7-cyclin D1-CDK4/6 signaling. Results
obtained from this exploratory investigation will greatly advance our knowledge about...

## Key facts

- **NIH application ID:** 10947732
- **Project number:** 1R21AA031725-01
- **Recipient organization:** NORTHEAST OHIO MEDICAL UNIVERSITY
- **Principal Investigator:** PING ZHANG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $224,250
- **Award type:** 1
- **Project period:** 2024-09-05 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947732

## Citation

> US National Institutes of Health, RePORTER application 10947732, Alcohol impairs the HSPC response to septic infection (1R21AA031725-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10947732. Licensed CC0.

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