# Role of Epigenetics and their Pharmacological Modulators in Innate Intestinal Immunity and Adjuvanticity in Humans

> **NIH NIH U19** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $427,025

## Abstract

PROJECT SUMMARY/ABSTRACT
The intestinal immune system has evolved to tolerate most antigens while mounting an effective immune
response to combat infections by pathogens. Epigenetics, defined as heritable changes in the genome without
alteration of the DNA sequence, has been shown to play a critical role in regulating intestinal immunity.
However, a better understanding of epigenetic modifications and how their pharmacological modulators affect
these modifications is still lacking. In addition, the current approach to developing vaccines containing novel
adjuvants is slow and needs improvement. Epigenetics offers an exciting opportunity towards the development
of novel adjuvants by targeting small molecules as pharmacological modulators to reprogram the epigenetic
landscape of innate immune memory, or trained immunity, which could confer enhanced resistance against a
broad array of bacteria in humans. In Research Project 3, our overall goal is to investigate the role of
epigenetic marks and their pharmacological modulators in intestinal immunity, specifically focusing on the
function of epithelial cells, natural killer (NK), and innate T cells, such as Mucosal-associated invariant T
(MAIT) cells, T-cell receptor gamma delta (TCR- ) cells, and natural killer T (NKT) cells, in response to two
important enteric pathogens, Salmonella enterica serovar Typhi (S. Typhi) and Shigella flexneri 2a (S. flexneri).
This study will build on our previous findings that MAIT subsets exhibiting specific cytokine pattern signatures
were associated with protection against typhoid fever and that S. Typhi infection regulates changes in
chromatin marks that depend on individual cell subsets. Additionally, compared to the placebo group,
vaccination with the oral Ty21a typhoid vaccine resulted in increased levels of NK cells upon a second antigen
encounter after experimental human challenge with wild-type S. Typhi, which is consistent with the presence of
trained immunity driven by epigenetic control. We have assembled a unique set of human specimens and tools
to test our hypotheses, including (i) cells obtained from peripheral blood of healthy individuals immunized with
oral vaccines, (ii) cells isolated from the duodenum, terminal ileum, and colon, and (iii) their counterparts as in
vitro culture models [explants and organoids] from adults and children.

## Key facts

- **NIH application ID:** 10823672
- **Project number:** 1U19AI181108-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Rosangela Mezghanni
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $427,025
- **Award type:** 1
- **Project period:** 2024-08-20 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823672

## Citation

> US National Institutes of Health, RePORTER application 10823672, Role of Epigenetics and their Pharmacological Modulators in Innate Intestinal Immunity and Adjuvanticity in Humans (1U19AI181108-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10823672. Licensed CC0.

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