# Understanding the functional role of Myeloid Derived Suppressor cells  in tuberculosis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $869,240

## Abstract

PROJECT SUMMARY. Mycobacterium tuberculosis (Mtb), the causative agent of the disease
tuberculosis (TB), is estimated to infect one-fourth of the world's population, resulting in approximately
1.6 million deaths each year. The emergence of multidrug- and extensively drug-resistant Mtb strains
and the variable efficacy of the currently used vaccine, M. bovis Bacille Calmette Guerin (BCG), are
barriers to the global control of TB. Thus, there is a critical need to better understand the mechanisms
of TB immunopathogenesis, as such mechanisms can be targeted to improve host control of Mtb
infection. The tubercle granuloma is long been considered a hallmark of TB. Our published data
suggest that the presence of inducible bronchus-associated lymphoid tissue (iBALT)-containing
granulomas is indicative of protective granulomas that mediate Mtb control during TB latency. In
contrast, infiltrating myeloid derived suppressor cells (MDSCs) as well as neutrophils producing
proinflammatory molecules are characteristic of non-protective granulomas during pulmonary TB.
MDSCs are induced during pulmonary TB in humans, nonhuman primates (NHPs) and mice and
suppress protective T cell responses. Our new data show a protective role for the proinflammatory
cytokine, Interleukin (IL)-17 in dampening lung MDSC accumulation and limiting T cell suppression
in the lung during TB. Additionally, we show that the MDSC-derived proinflammatory proteins,
S100A8/A9 heterodimers are induced upon Mtb infection in humans, NHPs and mice. Furthermore,
S100A8/A9-expressing myeloid cells accumulate within the tubercle granuloma and amplify lung
MDSC accumulation to mediate Mtb susceptibility. In the current proposal, using mouse and NHP
models of TB, we will elucidate the mechanism(s) which regulate and promote MDSC accumulation
during TB, and characterize whether MDSCs and their pathways can be targeted as host-directed
therapeutics (HDTs) for TB. In Specific Aim 1, using gene deficient and conditional gene deficient
mouse models we will determine the IL-17-dependent pathways that limit MDSC accumulation during
TB. In Specific Aim 2, we will evaluate the role of S100A8/A9 proteins in driving MDSC accumulation
and susceptibility to TB, and also determine whether blocking S100A8/A9 signaling will limit TB
relapse. Finally, in Specific Aim 3 we will evaluate if MDSC depletion can prevent TB progression in
nonhuman primates (NHPs). At the completion of the aims proposed here, we will have considerably
expanded our understanding of the Mtb-specific signaling pathways and factors that positively
(S100A8/A9 pathways) and negatively (IL-17 dependent pathways) regulate MDSC accumulation
during TB. Additionally, our translational studies in NHPs will enable the use of HDTs to limit MDSCs
during TB.

## Key facts

- **NIH application ID:** 10440359
- **Project number:** 5R01AI155024-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Deepak Kaushal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $869,240
- **Award type:** 5
- **Project period:** 2020-07-06 → 2022-09-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440359

## Citation

> US National Institutes of Health, RePORTER application 10440359, Understanding the functional role of Myeloid Derived Suppressor cells  in tuberculosis (5R01AI155024-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440359. Licensed CC0.

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