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Protection Against Nosocomial Infections After Severe Burn Injury Through Trained Immunity

Award Number: R35GM141927
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Protection Against Nosocomial Infections After Severe Burn Injury Through Trained Immunity - PROJECT SUMMARY Nosocomial infections remain the leading cause of death in severely burned patients due to barrier loss, im- paired immunity, and high prevalence of antibiotic resistant pathogens. Immunomodulatory strategies aimed at augmenting the host response are greatly needed. Evidence suggests that Toll-like receptor (TLR) agonists hold strong promise as immunotherapeutic agents to achieve that goal. Priming with TLR4 agonists enhances resistance against a variety of clinically relevant infections associated with severe burn injury in mice via induc- tion of “trained immunity” whereby innate immune cells become more responsive to subsequent infectious stimuli. TLR4-mediated trained immunity is characterized by metabolic reprogramming and mitochondrial ex- pansion in macrophages which boost antimicrobial responses. Cellular signaling mechanisms responsible for TLR-mediated trained immunity and the effect of burn injury on metabolic and mitochondrial function in innate leukocytes remains to be elucidated. Our research program aims to investigate immunomodulatory therapies for prevention of infection following severe burn by elucidating burn-induced immunometabolic dysfunction and the potential for triggering trained immunity for protection after burn. To achieve these goals, we will pursue three integrated projects: Project 1 will investigate the impact of severe burn and post-burn infection on myeloid cell immunometabolism and mitochondrial function. We will assess metabolic, mitochondrial, and antimicrobial function using a variety of techniques including glycolytic and oxidative stress capacity, mitochon- drial content and function analyses, and differential gene expression in mouse and human leukocytes after burn. This project will expand our understanding of molecular mechanisms behind burn-induced leukocyte dys- function. Project 2 will evaluate mechanisms by which TLR agonists induce trained immunity in leuko- cytes after burn. We will use genetic modification, TLR signaling pathway-selective agonism, and signaling pathway blockade to investigate the molecular mechanisms involved in TLR-mediated induction of trained im- munity after burn. We will examine the ability of TLR agonists to induce trained immunity in leukocytes from burn patients. This project will fill critical gaps in our understanding of mechanisms by which we can improve resistance to infections in burn patients. Project 3 will elucidate the potential of targeting TLR-signaling pathways for therapeutic benefit in clinically relevant models of burn-associated infection. We will de- termine the efficacy of clinically applicable TLR agonists in conferring protection against a variety of pathogens prevalent in burn patients. We will evaluate protection duration, extension of protection upon repeated therapy, and whether TLR agonists can promote infection clearance after infection onset. This project will reveal poten- tial drug targets that should be considered for clinical development for mediating protection against nosocomial infections in burn patients. These projects will enhance our understanding of burn-induced innate immune dys- function and identify therapeutic targets to improve immunity and protect against burn-related infections.


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: 2025 ( Subtotal = $482,261 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	001	4	1/23/2025	SUPPLEMENT FOR EXPANSION	$49,761
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	002	4	5/28/2025	TERMINATION	$0
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	003	5	5/29/2025	NON-COMPETING CONTINUATION	$432,500
2025	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	4	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $482,261

Issue Date FY: 2024 ( Subtotal = $432,500 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	4	3/29/2024	NON-COMPETING CONTINUATION	$389,250
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	001	4	7/23/2024	NON-COMPETING CONTINUATION	$43,250
														Subtotal = $432,500

Issue Date FY: 2023 ( Subtotal = $432,500 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	3	4/7/2023	NON-COMPETING CONTINUATION	$432,500
														Subtotal = $432,500

Issue Date FY: 2022 ( Subtotal = $450,449 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	2	4/7/2022	NON-COMPETING CONTINUATION	$389,250
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	002	2	6/23/2022	NON-COMPETING CONTINUATION	$43,250
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	001	2	5/31/2022	SUPPLEMENT FOR EXPANSION	$17,949
														Subtotal = $450,449

Issue Date FY: 2021 ( Subtotal = $173,000 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Biomedical Research and Research Training	000	1	4/12/2021	NEW	$173,000
														Subtotal = $173,000

Grand Total All Awards = $1,970,710

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Protection Against Nosocomial Infections After Severe Burn Injury Through Trained Immunity

Award Number: R35GM141927

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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