Targeted Gene Expression Profiling of Human Myeloid Cells From Blood and Lung Compartments of Patients With Tuberculosis and Other Lung Diseases.

Leigh Ann Kotze,Adam Penn-Nicholson,Thomas Scriba,Shirley Mcanda,Nelita Du Plessis,Mzwandile Erasmus,Brian W Allwood,Gerhard Walzl,Bryan Leonard,Stephanus T Malherbe,Gian Van Der Spuy,Munyaradzi Musvosvi,Coenraad F N Koegelenberg

doi:10.3389/fimmu.2022.839747

Abstract

Myeloid-derived suppressor cells (MDSC) have been identified in the peripheral blood and granulomas of patients with active TB disease, but their phenotype-, function-, and immunosuppressive mechanism- spectrum remains unclear. Importantly, the frequency and signaling pathways of MDSC at the site of disease is unknown with no indication how this compares to MDSC identified in peripheral blood or to those of related myeloid counterparts such as alveolar macrophages and monocytes. Most phenotypic and functional markers have been described in oncological studies but have not yet been validated in TB. Using a panel of 43 genes selected from pathways previously shown to contribute to tumor-derived MDSC, we set out to evaluate if the expression of these additional functional markers and properties may also be relevant to TB-derived MDSC. Differential expression was investigated between MDSC, alveolar macrophages and monocytes enriched from bronchoalveolar lavage fluid and peripheral blood of patients with active TB, patients with other lung diseases (OLD). Results demonstrated that anatomical compartments may drive compartment-specific immunological responses and subsequent MDSC immunosuppressive functions, demonstrated by the observation that MDSC and/or monocytes from PB alone can discriminate, via hierarchical clustering, between patients with active TB disease and OLD. Our data show that the gene expression patterns of MDSC in peripheral blood and bronchoalveolar lavage fluid do not cluster according to disease states (TB vs OLD). This suggests that MDSC from TB patients may display similar gene expression profiles to those found for MDSC in cancer, but this needs to be validated in a larger cohort. These are important observations for TB research and may provide direction for future studies aimed at repurposing and validating cancer immunotherapies for use in TB.

Highlights

Tuberculosis (TB), one of the most prominent communicable diseases in existence, is caused by Mycobacterium tuberculosis (M.tb) infection [1]
Peripheral blood (n=8) and broncho-alveolar lavage fluid (BALF) (n=9) samples were collected from participants upon diagnosis of active pulmonary TB disease prior to initiation of standard antibiotic treatment and controls with lung disease other than TB, residing in the same community (n=4) (Table 2)
Purity checks could not be performed on the alveolar macrophages (AM) owing to the known issues with autofluorescence in these cells because of the high level of carbon loading within the macrophage population of participants from the Western Cape province of South Africa [32]

Summary

Introduction

Tuberculosis (TB), one of the most prominent communicable diseases in existence, is caused by Mycobacterium tuberculosis (M.tb) infection [1]. Host immune modulators are currently explored as a popular approach to enhance immune responses through novel vaccines and drugs thereby reducing susceptibility to infection, delaying disease progression and accelerating cure [2–4]. Myeloid derived suppressor cells (MDSC) are a heterogenous population of immature myeloid cells, with potent immune suppressive functions [5]. A multitude of immunosuppressive mechanisms have been reported for tumor-derived MDSC, presumably reflective of the heterogeneity and functional redundancy of this cell population. While these mechanisms are designed to suppress excess inflammation, they are frequently demonstrated to rather inactivate pivotal immune responses required for protection against tumor cells and pathogenic infections alike [10, 11]

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Conclusion