# Innate immune-mediated control of pulmonary Legionella pneumophila infection

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $481,945

## Abstract

Project Summary
Intracellular bacterial pathogens such as Legionella pneumophila, an important cause of community- and
hospital-acquired pneumonia, are responsible for significant morbidity and mortality worldwide. As the spread
of broad-spectrum antibiotic resistance among bacterial pathogens is escalating, discovery of novel innate
immune defense mechanisms may hold the key for future therapeutic approaches to deal with this increasing
threat. Intracellular pathogens deploy virulence factors to disable many immune cell functions. To win this
battle, the host must overcome this subversion, through as yet poorly defined mechanisms. To address this
critical gap in knowledge, we seek to define the parameters of successful innate immune clearance of
Legionella. Legionella replicates within alveolar macrophages by using its type IV secretion system to deliver
bacterial effectors, several of which inhibit host protein synthesis. Several effectors inhibit host protein
synthesis. Despite this block in host translation, Legionella infection paradoxically enhances production of
inflammatory cytokines. In the previous funding period, we demonstrated that Legionella-infected alveolar
macrophages are able to synthesize and release IL-1; moreover, IL-1 receptor (IL-1R) signaling was required
for robust production of TNF and IL-12 by bystander myeloid cells. Intriguingly, our newly published study show
for the first time that IL-1R signaling in alveolar epithelial cells induces production of granulocyte-macrophage
colony-stimulating factor (GM-CSF), which was required for bystander cytokine production and bacterial
clearance. Intriguingly, while GM-CSF acts as a potent inflammatory cytokine in host defense against a broad
spectrum of pathogens, our findings show for the first time that GM-CSF metabolically reprograms monocytes
to undergo aerobic glycolysis, thereby promoting cytokine production. We will test the hypothesis that alveolar
epithelium-derived GM-CSF metabolically reprograms monocytes to amplify epigenetic changes that enhance
TLR-driven cytokine production and control of infection. In this renewal, we propose three Aims to first: define
which cell types produce and respond to GM-CSF, second: understand the role of GM-CSF-mediated
metabolic reprogramming in host defense, and third: define how GM-CSF and TLR signaling collaborate to
promote cytokine production. Together, these studies will define novel innate immune mechanisms employed
by the host to surmount pathogen-encoded virulence activities. The proposed research will therefore provide
vital insight into mechanisms of host defense that are utilized against broad classes of microbial pathogens
and aid development of improved anti-microbial therapeutics and vaccines.

## Key facts

- **NIH application ID:** 10317640
- **Project number:** 2R01AI118861-06A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sunny Shin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $481,945
- **Award type:** 2
- **Project period:** 2015-11-16 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317640

## Citation

> US National Institutes of Health, RePORTER application 10317640, Innate immune-mediated control of pulmonary Legionella pneumophila infection (2R01AI118861-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10317640. Licensed CC0.

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