# Regulation of Immune Responses to Mycobacterium tuberculosis Infection

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $594,246

## Abstract

SUMMARY
The disease outcome and pathology of tuberculosis (TB) are driven by the type of immune response mounted
in the host, yet the molecular requirements for successful control of TB by immune cells remain poorly
understood. In particular, although IL-10 production is upregulated in patients with active TB and is known to
antagonize pathways that are essential for the control of Mycobacterium tuberculosis (Mtb) infection, the
impact and function of IL-10 during Mtb infection has remained elusive because loss of function studies (i.e, in
Il10-/- mice) have yielded only minimal phenotypes. We previously showed that the transcription factor Bhlhe40
regulates IL-10 expression in T cells in a mouse model of multiple sclerosis. By analyzing several published
gene expression datasets, we have now found that BHLHE40 transcripts are present in significantly lower
abundance in patients with active TB as compared to healthy controls and patients with latent TB. This finding
of decreased BHLHE40 expression in patients with active TB led us to investigate its role during Mtb infection
in mice. We discovered that loss of Bhlhe40 in mice during Mtb infection results in higher Il10 expression,
higher bacterial burden, and early susceptibility to infection. The severe phenotypes observed in Bhlhe40-/-
mice are similar to those observed in mice lacking STAT1 or NF-κB p50, both of which are transcription factors
central to immune regulation. However, unlike STAT1 and NF-κB, a role for Bhlhe40 during infection is
completely unknown. Through a series of detailed mechanistic studies, we find that Bhlhe40 is required to
directly repress Il10 expression in T cells and CD11c+ cells during Mtb infection, and deletion of Il10 in
Bhlhe40-/- mice reverses the susceptibility of these mice. Our preliminary data have led to our central
hypothesis that Bhlhe40 functions as a key transcriptional regulator of gene expression during Mtb infection
that is required for effective control of Mtb replication. We will begin to address this hypothesis by dissecting
the mechanism by which Bhlhe40 regulates IL-10 production and how this impacts susceptibility to Mtb. Our
studies are the first to investigate a role for Bhlhe40 in both infectious disease and in myeloid cells, and will
provide fundamental insights into the molecular requirements for immunity to infection. In addition,
investigations into Bhlhe40 provide a unique opportunity to shed light on how different levels of IL-10 can
impact TB disease, something that has not been evident in other studies. To test our hypothesis and improve
our understanding in these areas, we will address the following independent aims: (1) Identify how loss of
Bhlhe40 in T cells and CD11c+ cells impacts on immune responses to Mtb, (2) Dissect the mechanism
whereby Bhlhe40 regulates Il10 expression in immune cells, and (3) Define the immune responses that are
responsible for susceptibility to Mtb infection in the presence of higher Il10 expression.

## Key facts

- **NIH application ID:** 10465067
- **Project number:** 5R01AI132653-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brian Todd Edelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $594,246
- **Award type:** 5
- **Project period:** 2018-09-24 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465067

## Citation

> US National Institutes of Health, RePORTER application 10465067, Regulation of Immune Responses to Mycobacterium tuberculosis Infection (5R01AI132653-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10465067. Licensed CC0.

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