Evaluation of autophagy mediators in myeloid-derived suppressor cells during human tuberculosis

Kotze, Leigh A.; Leukes, Vinzeigh N.; Fang, Zhuo; Lutz, Manfred B.; Fitzgerald, Bryna L.; Belisle, John T.; Loxton, André G.; Walzl, Gerhard; Plessis, Nelita du

doi:10.1016/j.cellimm.2021.104426

Cited by 8 publications

(8 citation statements)

References 70 publications

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“…Most importantly, PB blood has long been used for measurement of soluble mediators and immune cell profile during TB disease, as proxy for the immunological profile at the site-of-disease ( 38 ). Previous studies have focussed on profiling actively expressed receptors on the surface of MDSC in the periphery during active TB and their soluble mediators, but few have investigated the gene expression profiles of MDSC isolated from different immunological compartments ( 20 , 24 , 39 , 40 ). The immune phenotype of MDSC in relation to other related immune cell types have also not been compared between the periphery and the lungs during active TB disease.…”

Section: Discussionmentioning

confidence: 99%

“…We compared these MDSC expression signatures to those observed in control monocyte and AM populations owing to the majority of MDSC in the blood being of the monocyte lineage. Studies have demonstrated that M-MDSC are the predominant subset in the periphery ( 20 , 21 , 24 ), and data from immune-oncology studies have demonstrated that M-MDSC entering the tumor are capable of differentiating into tumor-associated macrophages (TAMs), supporting the use of alveolar macrophages as a control population from the lung ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the frequency and signaling pathways of MDSC at the site of TB disease (the lung) is also unknown with no indication how this compares to those identified in the blood or to those of related myeloid counterparts such as alveolar macrophages, monocytes, dendritic cells, or neutrophils. In recent studies it was shown that MDSC exhibit monocytic and granulocytic morphologies, although M-MDSC appear more relevant in the context of M.tb-infected participation, due to its phagocytic potentials ( 20 , 23 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…As M-MDSCs share phagocytic abilities and a myeloid ancestor with macrophages, it has been hypothesized that they may also harbour Mtb and undergo similar metabolic changes. A recent study with M-MDSCs from TB patients showed that this cell subset had increased expressions of soluble proteins and cell surface markers involved in phagocytosis and that these proteins and markers significantly decreased after disease treatment, suggesting that M-MDSCs have increased phagocytic abilities in Mtb infection 56 .…”

Section: Phagocytosis and Metabolic Changesmentioning

confidence: 99%

At Once Friends and Foes

Nelson

2023

MSURJ

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Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) disease. In chronic infections such as TB, consistent pro-inflammatory signalling promotes the generation of myeloid-derived suppressor cells (MDSCs). MDSCs are innate immune cells that are further divided into polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC) subtypes on the basis of their morphology. These cells exert immunosuppressive effects on other immune cell types, thereby protecting the integrity of the lung tissue from damage caused by dysregulated Mtb. However, this comes at the expense of containing the Mtb infection. MDSCs’ unique double-edged role makes them an attractive target for host-directed TB therapeutics. This review aims to summarize current knowledge on the role of MDSCs in TB.

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“…MDSC can be divided into at least two subsets with distinct morphology and suppressive mechanisms: firstly, monocytic MDSC (M-MDSC), morphologically similar to monocytes, macrophages, and dendritic cells, expressing high levels of NO; and secondly, polymorphonuclear MDSC (PMN-MDSC), morphologically similar to granulocytes, expressing high levels of ROS (8)(9)(10). MDSC frequencies are increased in humans at TB diagnosis (11), returning to levels consistent with otherwise healthy controls following successful treatment (11,12). Moreover, MDSC with immuno-modulatory and suppressive effects were shown to be present in the blood and lung components of TB patients (13).…”

Section: Introductionmentioning

confidence: 99%

Sildenafil, a Type-5 Phosphodiesterase Inhibitor, Fails to Reverse Myeloid-Derived Suppressor Cell-Mediated T Cell Suppression in Cells Isolated From Tuberculosis Patients

et al. 2022

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Successful TB treatment is hampered by increasing resistance to the two most effective first-line anti-TB drugs, namely isoniazid and rifampicin, thus innovative therapies focused on host processes, termed host-directed therapies (HDTs), are promising novel approaches for increasing treatment efficacy without inducing drug resistance. We assessed the ability of Sildenafil, a type-5 phosphodiesterase inhibitor, as a repurposed compound, to serve as HDT target, by counteracting the suppressive effects of myeloid-derived suppressor cells (MDSC) obtained from active TB cases on T-cell responsiveness. We confirm that MDSC suppress non-specific T-cell activation. We also show that Sildenafil treatment fails to reverse the MDSC-mediated suppression of T-cell functions measured here, namely activation and proliferation. The impact of Sildenafil treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.

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Evaluation of autophagy mediators in myeloid-derived suppressor cells during human tuberculosis

Cited by 8 publications

References 70 publications

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

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

At Once Friends and Foes

Sildenafil, a Type-5 Phosphodiesterase Inhibitor, Fails to Reverse Myeloid-Derived Suppressor Cell-Mediated T Cell Suppression in Cells Isolated From Tuberculosis Patients

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