# Persistent DNA Hyper-Methylation of the IFN-γ Signaling Pathway During Tuberculosis

> **NIH NIH K23** · BAYLOR COLLEGE OF MEDICINE · 2020 · $189,324

## Abstract

PROJECT SUMMARY:
 Tuberculosis (TB) is the world’s leading infectious disease cause of mortality and suffering.
Existing “short-course” therapy lasts six grueling months and has case fatality rates of 3% that increase
to >20% in TB hyper-endemic countries and > 30% in the setting of multi-drug resistant TB. The
Mendelian Susceptibility to Mycobacterial Disease (MSMDs) are rare genetic mutations that perturb the
immune system either up or down-stream of the IFN-γ signaling pathway. It is well known that TB
subverts host immune control, however the multiple mechanisms it does so remain to be fully
elucidated.
 Our preliminary data demonstrate that TB epigenetically subverts host immunity by inducing
DNA hyper-methylation both up and down-stream of the IFN-γ signaling pathway, akin to the MSMD
mutations. Further, our preliminary data demonstrates that immune cells from study participants with
TB have decreased up-regulate of IFN-γ-inducible gene expression, thereby mimicking the functional
defect seen in the down-stream MSMD mutations in IFNGR, STAT1, and IRF1. Our preliminary
bioinformatics analysis demonstrates that the inhibition of IFN-γ-inducible gene expression occurs
through epigenetic inhibition of a) the canonical IFN-γ signaling pathway, b) transcription factors and c)
non-canonical signaling pathways.
 Using an existing biorepository, we will evaluate the DNA methylation of the canonical IFN-γ
signaling pathway as well as overlapping and intertwined non-canonical signaling pathways. We will
functionally validate these results by evaluating if de-methylating agents are able to reverse DNA
hyper-methylation of the IFN-γ signaling pathway and restore IFN-γ inducible gene expression. We will
longitudinally perform these analyses on adults with 1) asymptomatic household contacts, 2) pulmonary
TB with treatment success and 3) pulmonary TB with treatment failure.
 The elucidation of epigenetic mechanisms by which TB subverts host immunity is a necessary
step in developing improved treatment monitoring tools and the development of adjunct host directed
immunotherapy to improve clinical outcomes. The proposed science and mentorship will have the
applicant poised for successful transition to an independent researcher.

## Key facts

- **NIH application ID:** 9961491
- **Project number:** 5K23AI141681-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Andrew R DiNardo
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $189,324
- **Award type:** 5
- **Project period:** 2019-06-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961491

## Citation

> US National Institutes of Health, RePORTER application 9961491, Persistent DNA Hyper-Methylation of the IFN-γ Signaling Pathway During Tuberculosis (5K23AI141681-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961491. Licensed CC0.

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