Heterogeneous GM-CSF signaling in macrophages is associated with control of Mycobacterium tuberculosis

Bryson, Bryan; Rosebrock, Tracy R.; Tafesse, Fikadu G.; Itoh, Christopher Y.; Nibasumba, Armel; Babunovic, Gregory H.; Corleis, Björn; Martin, Constance; Keegan, Caroline; Andrade, Priscila Ribeiro; Realegeno, Susan; Kwon, Douglas S.; Modlin, Robert L.; Fortune, Sarah M.

doi:10.1038/s41467-019-10065-8

Cited by 64 publications

(63 citation statements)

References 39 publications

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“…GM-CSF has been increasingly appreciated as an essential mediator of protective immunity against TB 25 – 31 . However, the mechanisms underlying the pathology observed in the absence of GM-CSF signalling during M. tuberculosis infection remain poorly understood, particularly since past studies performed in GM-CSF-deficient mice had confounding lung pathologies 33 , 34 , hampering interpretation of the findings.…”

Section: Discussionmentioning

confidence: 99%

“…Macrophages and CD4 + T cells, and several cytokines such as IL-12, IFN-γ, TNF and IL-1 have been shown to play a major role in protection against M. tuberculosis infection 2 – 4 , 13 , 21 – 24 . More recently, GM-CSF has also been increasingly recognised as a key mediator for TB resistance 25 – 31 , and is in the pipeline for host-directed therapy as an adjuvant treatment of TB 32 . The presence of GM-CSF specific autoantibodies that block GM-CSF function have been linked to cryptococcal disease and some cases of pulmonary TB 28 .…”

Section: Introductionmentioning

confidence: 99%

“…The presence of GM-CSF specific autoantibodies that block GM-CSF function have been linked to cryptococcal disease and some cases of pulmonary TB 28 . In addition, GM-CSF treatment of mouse and human macrophages restricts intracellular mycobacterial growth in vitro 25 , 26 , 29 , 30 and mice lacking GM-CSF are highly susceptible to M. tuberculosis infection 27 , 31 . Impaired innate immune responses and decreased recruitment of protective IFN-γ producing CD4 + T cells into the site of infection have been proposed as mechanisms for the increased susceptibility following M. tuberculosis infection in mice deficient in GM-CSF 27 , 31 .…”

Section: Introductionmentioning

confidence: 99%

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Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

et al. 2020

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Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Transcriptional signatures associated with type I IFN signalling and neutrophilic inflammation were shown to correlate with disease severity in mouse models of TB. Here we show that similar transcriptional signatures correlate with increased bacterial loads and exacerbate pathology during Mycobacterium tuberculosis infection upon GM-CSF blockade. Loss of GM-CSF signalling or genetic susceptibility to TB (C3HeB/FeJ mice) result in type I IFN-induced neutrophil extracellular trap (NET) formation that promotes bacterial growth and promotes disease severity. Consistently, NETs are present in necrotic lung lesions of TB patients responding poorly to antibiotic therapy, supporting the role of NETs in a late stage of TB pathogenesis. Our findings reveal an important cytokine-based innate immune effector network with a central role in determining the outcome of M. tuberculosis infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

et al. 2020

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“…Studies in mice show that deficiency in GM-CSF results in the inability to contain infection ( Gonzalez-Juarrero et al., 2005 ). Other research suggests that survival of bacteria in macrophages is regulated by GM-CSF response in macrophages ( Bryson et al., 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Machine Learning Algorithms Evaluate Immune Response to Novel Mycobacterium tuberculosis Antigens for Diagnosis of Tuberculosis

Meier

Sutter

Jacobsen

et al. 2021

Front. Cell. Infect. Microbiol.

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RationaleTuberculosis diagnosis in children remains challenging. Microbiological confirmation of tuberculosis disease is often lacking, and standard immunodiagnostic including the tuberculin skin test and interferon-γ release assay for tuberculosis infection has limited sensitivity. Recent research suggests that inclusion of novel Mycobacterium tuberculosis antigens has the potential to improve standard immunodiagnostic tests for tuberculosis.ObjectiveTo identify optimal antigen–cytokine combinations using novel Mycobacterium tuberculosis antigens and cytokine read-outs by machine learning algorithms to improve immunodiagnostic assays for tuberculosis.MethodsA total of 80 children undergoing investigation of tuberculosis were included (15 confirmed tuberculosis disease, five unconfirmed tuberculosis disease, 28 tuberculosis infection and 32 unlikely tuberculosis). Whole blood was stimulated with 10 novel Mycobacterium tuberculosis antigens and a fusion protein of early secretory antigenic target (ESAT)-6 and culture filtrate protein (CFP) 10. Cytokines were measured using xMAP multiplex assays. Machine learning algorithms defined a discriminative classifier with performance measured using area under the receiver operating characteristics.Measurements and main resultsWe found the following four antigen–cytokine pairs had a higher weight in the discriminative classifier compared to the standard ESAT-6/CFP-10-induced interferon-γ: Rv2346/47c- and Rv3614/15c-induced interferon-gamma inducible protein-10; Rv2031c-induced granulocyte-macrophage colony-stimulating factor and ESAT-6/CFP-10-induced tumor necrosis factor-α. A combination of the 10 best antigen–cytokine pairs resulted in area under the curve of 0.92 ± 0.04.ConclusionWe exploited the use of machine learning algorithms as a key tool to evaluate large immunological datasets. This identified several antigen–cytokine pairs with the potential to improve immunodiagnostic tests for tuberculosis in children.

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“…Most of the studies that have been conducted in murine models of TB suggest that the production of GM-CSF by lung epithelial cells, conventional, and non-conventional T cells are essential for generating a protective immune response and restricting MTB growth in the lungs ( 8 – 11 ). A recent study, clearly suggested that human macrophages were also able to produce GM-CSF upon infection with MTB, and their antimycobacterial properties correlated with their ability to produce GM-CSF ( 12 ). While MTB-infected human macrophages displayed cell-to-cell variability in their antibacterial capacity, cell populations with increased expression of genes involved in the GM-CSF signaling pathway were able to better control MTB growth.…”

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confidence: 99%

GM-CSF Dependent Differential Control of Mycobacterium tuberculosis Infection in Human and Mouse Macrophages: Is Macrophage Source of GM-CSF Critical to Tuberculosis Immunity?

et al. 2020

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Although classically associated with myelopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) is being increasingly recognized for its potential role in innate resistance against tuberculosis (TB). While the GM-CSF is produced by a variety of host cells, including conventional and non-conventional T cells, macrophages, alveolar epithelial cells, the cell population that promotes GM-CSF mediated innate protection against Mycobacterium tuberculosis infection remains unclear. This is because studies related to the role of GM-CSF so far have been carried out in murine models of experimental TB, which is inherently susceptible to TB as compared to humans, who exhibit a resolution of infection in majority of cases. We found a significantly higher amount of GM-CSF production by human macrophages, compared to mouse macrophages, after infection with M. tuberculosis in vitro. The higher levels of GM-CSF produced by human macrophages were also directly correlated with their increased life span and ability to control M. tuberculosis infection. Other evidence from recent studies also support that M. tuberculosis infected human macrophages display heterogeneity in their antibacterial capacity, and cells with increased expression of genes involved in GM-CSF signaling pathway can control intracellular M. tuberculosis growth more efficiently. Collectively, these emerging evidence indicate that GM-CSF produced by lung resident macrophages could be vital for the host resistance against M. tuberculosis infection in humans. Identification of GM-CSF dependent key cellular pathways/processes that mediate intracellular host defense can lay the groundwork for the development of novel host directed therapies against TB as well as other intracellular infections.

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Heterogeneous GM-CSF signaling in macrophages is associated with control of Mycobacterium tuberculosis

Cited by 64 publications

References 39 publications

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

Machine Learning Algorithms Evaluate Immune Response to Novel Mycobacterium tuberculosis Antigens for Diagnosis of Tuberculosis

GM-CSF Dependent Differential Control of Mycobacterium tuberculosis Infection in Human and Mouse Macrophages: Is Macrophage Source of GM-CSF Critical to Tuberculosis Immunity?

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