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Principal Investigator: Julia K. Bohannon
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $432,500
Funding agency: National Institute of General Medical Sciences
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.
Terms: <Agonist><Blood leukocyte><Burn injury><Burns><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Differential Gene Expression><Drug Targeting><Dysfunction><Exposure to><Functional disorder><Genetic><Goals><High Prevalence><Homolog of Drosophila TOLL><Hospital Admission><Hospital Infections><Hospital acquired infection><Hospitalization><Human><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Modulation Therapy><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune mediated therapy><Immune memory><Immune response><Immune system><Immunes><Immunity><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunologic Memory><Immunological Diseases><Immunological Dysfunction><Immunological Memory><Immunological System Dysfunction><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunotherapeutic agent><Immunotherapy><Impairment><Infection><Infection prevention><Intracellular Communication and Signaling><Knowledge><Leukocytes><Leukocytes Reticuloendothelial System><Life><Macrophage><Marrow leukocyte><Mediating><Metabolic><Mice><Mice Mammals><Mitochondria><Modern Man><Modification><Molecular><Murine><Mus><Myeloid Cells><Mφ><Nosocomial Infections><Oxidative Stress><Patients><Physiopathology><Predisposition><Prevent infection><Research><Resistance><Resistance to infection><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Susceptibility><TLR protein><TLR4><TLR4 gene><Techniques><Therapeutic><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Toll Homologue><Toll-Like Receptor Family Gene><Toll-like receptors><Training><White Blood Cells><White Cell><anamnestic reaction><anti-microbial><antibiotic resistant pathogen><antimicrobial><biological signal transduction><burn model><burned><clinical applicability><clinical application><clinical development><clinical relevance><clinically relevant><determine efficacy><drug resistant pathogen><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><host response><immune drugs><immune modulating therapies><immune modulation><immune modulatory therapies><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immune-modulation treatment><immuno therapy><immunologic reactivity control><immunologic therapeutics><immunomodulation therapy><immunomodulation treatment><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoregulation><immunoregulatory><immunoresponse><immunotherapeutics><immunotherapy agent><improved><infection resistance><institutional infection><mitochondrial><pathogen><pathophysiology><programs><resistant><response><secondary immune response><serious burns><severe burns><therapeutic target><toll-like receptor 4><white blood cell><white blood corpuscle>