# Elucidating the mechanisms and consequences of MDSC-regulated immunity in TB

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $539,481

## Abstract

PROJECT SUMMARY:
Myeloid derived suppressor cells (MDSCs) are immature myeloid cells with potent inhibitory properties for
macrophages and T cells. The link between MDSCs and tuberculosis (TB), a disease caused by Mycobacterium
tuberculosis (Mtb), is supported by work in mice where MDSC recruitment to the lungs correlates with disease
severity, and in humans, where peripheral blood MDSC abundance positively correlates with TB progression.
Work in mice also demonstrates that MDSCs are recruited to sites of BCG vaccination where they phagocytose
bacteria and suppress local T cell activation, suggesting that MDSCs may reduce the effectiveness of anti-TB
vaccination and contribute to TB’s status as a global public health concern. The relationship between MDSCs
and TB has generated interest in targeting them with host-directed therapies to improve TB treatment. Recent
work using tasquinimod (TSQ), an FDA-approved small molecule MDSC inhibitor, in guinea pigs and mice finds
that targeting MDSCs lowers reduces granuloma formation, lowers bacteria loads, and improves the treatment
efficacy of anti-TB drugs. These results are encouraging but critical questions need to be answered before
MDSCs can be safely targeted in human TB. Knowledge gaps include an incomplete understanding of how
MDSCs interact with macrophages in diseased tissue, if MDSCs restrain or promote pathologic inflammation in
TB, how MDSC activity relates to bacterial burden in granulomas, and if MDSCs permit or restrict Mtb replication.
These gaps are particularly acute in human TB where progress is inhibited by the inability to access granulomas
to study MDSCs in situ and fundamental differences between mouse and human TB pathophysiology. Our
proposal addresses these gaps with innovative studies using MDSCs from human cord blood and a nonhuman
primates (NHPs) model that accurately reflects human TB pathophysiology. We hypothesize that MDSCs
suppress macrophage-mediated anti-Mtb activity and are permissive hosts for Mtb and inhibiting their functions
will improve immunity, restrict bacterial persistence, and improve outcomes in TB. In Aim 1, we propose
mechanistic studies investigating relationships between MDSCs, macrophages, and Mtb that influence immunity.
We will determine if cell-free DNA release is a novel MDSC effector that suppresses macrophage function. We
also determine if MDSCs support Mtb as a permissive host cell and define molecular features at the phagosomal
level that contribute to competency for hosting Mtb. In Aim 2, we infect NHPs with mCherry-expressing Mtb and
use TSQ-mediated MDSC inhibition as an intervention to assess how MDSCs regulate lung inflammation,
immunity, and if they host Mtb. Here, we use PET/CT and fluorescence imaging, quantitative microbiology, and
flow cytometry to identify MDSC-regulated correlates of immunity in granulomas. We also define MDSC
transcriptional profiles in scRNAseq and use CosMx spatial molecular imaging to identify how MDSCs regulate...

## Key facts

- **NIH application ID:** 10857265
- **Project number:** 5R01AI164970-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Bryan David Bryson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $539,481
- **Award type:** 5
- **Project period:** 2022-07-22 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857265

## Citation

> US National Institutes of Health, RePORTER application 10857265, Elucidating the mechanisms and consequences of MDSC-regulated immunity in TB (5R01AI164970-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10857265. Licensed CC0.

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