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

Award Number: R01AI146592
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $481,837 )
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Allergy and Infectious Diseases Research	000	5	7/18/2023	NON-COMPETING CONTINUATION	$481,837
														Subtotal = $481,837

Issue Date FY: 2022 ( Subtotal = $488,107 )
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Allergy and Infectious Diseases Research	000	4	7/11/2022	NON-COMPETING CONTINUATION	$488,107
														Subtotal = $488,107

Issue Date FY: 2021 ( Subtotal = $481,048 )
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Allergy and Infectious Diseases Research	000	3	8/4/2021	NON-COMPETING CONTINUATION	$481,048
														Subtotal = $481,048

Issue Date FY: 2020 ( Subtotal = $475,483 )
2020	2020	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Allergy and Infectious Diseases Research	000	2	7/9/2020	NON-COMPETING CONTINUATION	$475,483
														Subtotal = $475,483

Issue Date FY: 2019 ( Subtotal = $501,663 )
2019	2019	GEORGIA TECH RESEARCH CORPORATION	505 10TH ST NW	ATLANTA	GA	30318	FULTON	USA	Allergy and Infectious Diseases Research	000	1	8/22/2019	NEW	$501,663
														Subtotal = $501,663

Grand Total All Awards = $2,428,138

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

Award Number: R01AI146592

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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