# Epigenetic & Post-Translational Mechanisms of Macrophage Resistance to Mycobacterium tuberculosis During HIV Co-Infection

> **NIH NIH R33** · UNIVERSITY OF WASHINGTON · 2020 · $1,021,774

## Abstract

Hurdles for controlling tuberculosis (TB) include the lack of a highly efficacious vaccine, prevention of
infection, long drug treatment regimens, and killing dormant bacilli within macrophages. After close contact
with an individual with pulmonary TB, most people develop latent Mtb infection (LTBI). However, some
individuals are naturally resistant to infection (RSTRs). The mechanisms of resistance are unknown and may
provide insight into novel therapeutic strategies. In a large TB household contact study in urban Uganda over
the past 20 years, we found that ~9% of close adult household contacts remained persistently TST and
Interferon-γ Release Assay (IGRA) negative during extended follow-up. To our knowledge, this large Ugandan
cohort is unique with rigorous longitudinal clinical and epidemiologic data. Using gene-set enrichment and
network analyses of transcriptional profiles of Mtb-infected peripheral blood-derived monocytes in the RSTR
and LTBI groups, we found that the histone deacetylase (HDAC) gene family distinguishes RSTRs from LTBIs
and may regulate resistance to Mtb infection. We performed a genome-wide linkage study in HIV-1 uninfected
(HIV-) RSTRs in Uganda and discovered loci associated with this important clinical phenotype. In peripheral
blood monocyte-derived and alveolar macrophages, HDAC inhibitor treatment decreased Mtb replication in
comparison to untreated cells. Together, these data support our primary hypotheses that RSTRs have
protective innate immune responses that are macrophage-dependent and partially HDAC-dependent.
However, there are many gaps in our knowledge. First, the HDAC signature was network-based and we do
not know if it is the major causal regulator of the RSTR phenotype. Second, HDACs are a family of 11
enzymes which modify chromatin and regulate transcription, cellular homeostasis, and the innate immune
response to microbes. The details of which HDAC-dependent pathways are altered in RSTRs are unknown.
Epigenetic and proteomic studies (including acetylation profiles) can address these gaps. Third, mechanisms
of Mtb resistance in HIV+ individuals are completely unknown. Since HIV infection profoundly dysregulates T-
cell responses to Mtb, HIV infected (HIV+) persons likely depend more on innate immunity to help control Mtb
than HIV uninfected (HIV-) persons. In the R61 phase (Aim 1 and 2), we will use epigenetic, proteomic, and
genetic approaches to discover candidate resistance genes and pathways that differ between RSTR and LTBI
HIV+ and HIV- individuals. In the R33 phase (Aim 3), we will use cellular and in vivo approaches to discover
mechanisms of resistance and small molecular inhibitors of these pathways that could be developed as host
directed therapies.

## Key facts

- **NIH application ID:** 10092518
- **Project number:** 4R33AI138272-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** W. Henry Boom
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,021,774
- **Award type:** 4N
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092518

## Citation

> US National Institutes of Health, RePORTER application 10092518, Epigenetic & Post-Translational Mechanisms of Macrophage Resistance to Mycobacterium tuberculosis During HIV Co-Infection (4R33AI138272-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10092518. Licensed CC0.

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