# Enhancement of Innate Anti-Microbial Immunity Using Novel Synthetic TLR4 Agonists

> **NIH NIH K08** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $174,958

## Abstract

PROJECT SUMMARY:
 I am an Associate Professor in the Division of Anesthesiology Critical Care Medicine at Vanderbilt
University Medical Center. As a critical care physician, I manage surgical patients with sequelae from surgical
and anesthetic inflammation, immune suppression, and infection. My earlier work focused on rapid detection
of infection and microbial resistance to aid in facilitating proper antimicrobial treatment. However, the increase
in antibiotic resistance has rendered management of infection a greater challenge, thus a need for alternative
infection control strategies. This award will allow me to explore the impact of a synthetic form of the TLR4
ligand MPLA termed phosphorylated hexaacyl disaccharide (PHAD) to enhance antimicrobial innate immunity
and alter endothelial dysfunction. Furthermore, I plan to engage in an intensive training program to develop
my career as a physician-scientist through mentored oversight and a structured curriculum leading to
successful research independence in the field of innate immunity and organ projection. Antimicrobial resistant
hospital-acquired infections continue to increase leading to morbidity to include inflammation, organ injury, and
death. Using hydrolysis derived MPLA, our laboratory has demonstrated enhanced bacterial clearance and
survival in murine models of infection; however the mechanisms by which sustained antimicrobial protection
develops is not well understood. Our work shows that macrophages and endothelia cells primed by MPLA
may strongly contribute to sustained antimicrobial function and alteration of endothelial dysfunction. Aim 1:
We hypothesize that PHADs will induce re-programming of the human macrophage phenotype leading to
predominance of phosphoinositide-3-kinase (PI3K)/Akt/mTOR/HIF-1α signaling, a metabolic profile
characterized by aerobic glycolysis and augmented phagocytosis and bacterial killing. Aim 2: We hypothesize
that PHADs will induce an endothelial phenotype that will facilitate antimicrobial functions and maintenance of
barrier function. We will investigate the ability of PHAD to impact endothelial cell metabolism, expression of
adhesion molecules (VCAM-1, ICAM-1, E-selectin), production of cytokines (IL-6, IP-10, G-CSF), and
maintenance of barrier function using human endothelial cells and clinically relevant murine model of CLP. In
the ex-vivo studies, the functional importance of specific signaling pathways in PHAD-induced alterations in
endothelial cell metabolism and barrier function will be assessed using specific inhibitors.
These studies will examine the impact of PHAD on the immunobiology of human macrophages and endothelial
cells, and identify dependence on the TRL4 derived MyD88 and TRIF signaling pathways. This work could
possibly lead to a novel immunotherapeutic agent for clinical use in perioperative and critical care medicine.

## Key facts

- **NIH application ID:** 9990829
- **Project number:** 5K08GM123345-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Antonio Hernandez
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $174,958
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990829

## Citation

> US National Institutes of Health, RePORTER application 9990829, Enhancement of Innate Anti-Microbial Immunity Using Novel Synthetic TLR4 Agonists (5K08GM123345-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990829. Licensed CC0.

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