# Synergistic control of acute respiratory pathogens by bacteriophage and the innate immune response

> **NIH NIH R01** · GEORGIA INSTITUTE OF TECHNOLOGY · 2020 · $475,483

## Abstract

Abstract
Multi-drug resistant (MDR) bacterial pathogens constitute a critical public health threat. The spread of
MDR pathogens in hospitals and in the environment has spurred a multidisciplinary response to develop
novel antibiotic alternatives. Bacteriophage (`phage') therapy represents a treatment strategy that can, in
principle, specifically eliminate MDR pathogens from animal hosts while minimizing off-target effects on
host cells and commensal bacteria. The successful compassionate use of phage therapy for critically ill
patients in the United States demonstrates a critical first-step towards large-scale translational deployment
of phage therapy. However, prior clinical trials of phage therapeutic efficacy have yielded equivocal
results, thereby raising the question: what are the core mechanisms underlying curative treatment of
respiratory infections by phage therapy? The use of phage-based therapy presumes that the direct killing
action of phage is responsible for pathogen elimination in vivo. In contrast, prior work of the investigators
showed that the outcome of in vivo phage therapeutic treatment of acute pneumonia in a murine host
depended critically on host immune state. The investigators combined population modeling and
experimental analysis to identify a mechanism of `immunophage synergy' to identify criteria when phage
therapy works and when it fails. Here, the project will combine population modeling, control theory, data-
driven computational simulations, in vitro experiments with phage, bacteria, and neutrophils, and in vivo
infection experiments in murine hosts to understand fundamental principles underlying curative treatment
of acute respiratory infections. This project will characterize the spatiotemporal drivers of synergistic
elimination in vivo as well as develop optimized combinations of phage strains, dosages, and timing to
avert therapeutic failure via the proliferation of phage-resistant bacterial mutants across a continuum of
immunodeficient hosts. The integrated and multidisciplinary research plans are designed to yield
fundamental insights into the mechanism of synergistic elimination of bacterial pathogens by phage and
innate effector cells as well as generalizable and rigorous approaches to optimized phage cocktail design
when immune responses are compromised.

## Key facts

- **NIH application ID:** 10000827
- **Project number:** 5R01AI146592-02
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Laurent DEBARBIEUX
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $475,483
- **Award type:** 5
- **Project period:** 2019-08-22 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000827

## Citation

> US National Institutes of Health, RePORTER application 10000827, Synergistic control of acute respiratory pathogens by bacteriophage and the innate immune response (5R01AI146592-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000827. Licensed CC0.

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