# Training Innate Immunity: A new approach to the treatment of Sepsis

> **NIH NIH R01** · EAST TENNESSEE STATE UNIVERSITY · 2021 · $553,544

## Abstract

This revised competitive renewal application is submitted under the NIH multiple PI initiative
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-11-118.html). Drs. Ed Sherwood and David Williams
will serve as the PIs. The multiple PI strategy is advantageous because it enables a “team science” approach
that will draw equally on the expertise and experience of both of the PIs, their research groups and their
respective institutions. The critically ill patient frequently develops a complex disease spectrum that may
include acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis syndrome,
septic shock and/or multiple organ dysfunction syndrome. In the United States ~951,000 patients/year develop
sepsis with approximately half of these patients in the ICU and an overall mortality rate is 28.6%. Those
patients that survive the initial septic event may ultimately succumb to widespread organ dysfunction that can
be either acute, due to hyper-inflammatory responses, or more prolonged due to immune dysfunction. It is well
accepted that sepsis causes suppression of the immune system and that sepsis-induced immunoparalysis
predisposes the critically ill patient to secondary infections. Attempts at developing effective therapies to
prevent or treat sepsis and its associated immunosuppression have proven to be exceedingly difficult. In fact,
no drugs are currently approved by the FDA for the management of sepsis. Recent data have provided
compelling evidence that the innate immune system can be “trained” to respond more rapidly and effectively to
pathogens. In this revised application, we propose the novel concept that it may be possible to “train” the
compromised immune system, such that an effective response can be mounted to existing and/or subsequent
infections. We hypothesize that “innate immune training will reprogram the metabolic, transcriptomic,
epigenomic and functional phenotype of monocytes and macrophages from patients with sepsis and
confer augmented resistance to infection”. To critically evaluate this hypothesis, we propose the following
specific aims. Aim 1. Define the functional role of β-glucan-induced metabolic reprogramming for
inducing and sustaining trained immunity in human monocytes and macrophages. In this aim, we will
explore the cellular and molecular mechanisms that are essential for induction of the trained phenotype.
Specifically, we will investigate the metabolic phenotype of trained human monocyte/macrophages and
determine the functional importance of metabolic reprogramming for inducing and sustaining the trained
phenotype in leukocytes. Aim 2. Elucidate the mechanisms of innate immune training in human adults as
a function of age. In this aim, we will examine the impact of immune training on leukocytes from aging
humans. In ex vivo experiments, we will examine cytokine secretion, metabolic reprogramming, gene
expression, the epigenome, mitochondrial function and the anti-microbial functions...

## Key facts

- **NIH application ID:** 10296894
- **Project number:** 2R01GM119197-05A1
- **Recipient organization:** EAST TENNESSEE STATE UNIVERSITY
- **Principal Investigator:** EDWARD R SHERWOOD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $553,544
- **Award type:** 2
- **Project period:** 2016-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296894

## Citation

> US National Institutes of Health, RePORTER application 10296894, Training Innate Immunity: A new approach to the treatment of Sepsis (2R01GM119197-05A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10296894. Licensed CC0.

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