PD-1 Deficiency Exacerbates Mycobacterium abscessus Lung Infection via Metabolic Rewiring and Dysregulated Neutrophil Responses
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE317955 | GEO | 2026/04/14
REPOSITORIES: GEO
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Project description:A PD-1-deficient Mycobacterium abscessus -infected mouse model was established. The impact of PD-1 on bacterial clearance, immune cell activity, and metabolism was evaluated via colony counting, histopathology, flow cytometry, multiplex immunofluorescence and transcriptomics. We fonud that PD-1−/− mice exhibited increased susceptibility to MAB. Early infection showed elevated lung CD4⁺ T cells, reduced neutrophils, and higher blood cytokines (IFN-γ, IL-21, IL-6, IL-27).
2026-04-14 | GSE317833 | GEO
Project description:BACKGROUND:Mental stress-induced neurotransmitters can affect the immune system in various ways, leading to tumor immune escape. Therefore, a better understanding of the potential functions of neurotransmitters in the tumor immune microenvironment is expected to promote the development of novel anti-tumor therapies, while facilitating synergistic immune therapy. METHODS: In this study, we analyzed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments, transcriptome analysis, metabolomic analysis, and experiments in vitro were used to reveal the specific mechanism of norepinephrine’s (NE) effect on immunotherapy. RESULTS: The plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. An animal model was established for verification, which further demonstrated that NE could cause anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of the C-X-C Motif Chemokine Ligand 9 (CXCL9) and the immunosuppressive metabolite adenosine (ADO) in tumor cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/β-catenin signaling pathway plays a crucial role in the NE-induced decrease in the secretion of CXCL9 and disturbance of ADO metabolism. CONCLUSION: NE can affect the secretion of CXCL9 and ADO in tumor cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD).
2023-04-04 | GSE218402 | GEO
Project description:We used microarrays to describe the gene expression in response to two isogenic morphotypes of M. abscessus (Mab) and to Staphylococcus aureus. Human neutrophils from healthy donors were exposed to rough Mab (ATCC 19977T), smooth Mab (ATCC 19977T) and S. aureus (CF clinical strain) for two hours; control cells were exposed to saline.
2013-01-10 | E-GEOD-39889 | biostudies-arrayexpress
Project description:Mycobacterium abscessus (Mab) infection can be a deadly infection in patients with chronic lung disease like cystic fibrosis. In vitro and in vivo, Mab may adopt a smooth (S) or rough (R) morphotype, the latter with fewer cell wall glycopeptidolipids. Although there are studies of the host response against constitutive Mab-S and Mab-R, we report the first analysis of early transcriptional events and responses in mouse bone marrow derived macrophages (BMDMs) upon infection with our media-selected, isogenic, interchangeable Mab-S and Mab-R. The early transcriptional events after infection with both the morphotypes showed considerable overlap of the pro-inflammatory genes that were differentially regulated compared to the uninfected macrophages. However, we also observed some signature genes which were upregulated during Mab-S compared to Mab-R infections. Media selected Mab-S and Mab-R behave in a similar fashion to constitutive S and R types with respect to pathogenesis and immune response and will likely be a better model of in vivo infection than multiply passaged, mutated organisms.
2023-01-31 | GSE221966 | GEO
Project description:Mycobacterium abscessus is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB-S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R. We sampled the small RNA (sRNA) transcriptome of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 hours post-infection (hpi) using RNA-seq. MAB-S elicited a more robust transcriptional response at the miRNA level, reflecting higher cytokine levels in culture supernatants. However, and a direct comparison identified no differentially expressed miRNAs between MAB-R- and MAB-S-infected cells. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes.
2015-09-09 | GSE72821 | GEO
Project description:Mycobacterium abscessus is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB-S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R. We sampled the small RNA (sRNA) transcriptome of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 hours post-infection (hpi) using RNA-seq. MAB-S elicited a more robust transcriptional response at the miRNA level, reflecting higher cytokine levels in culture supernatants. However, and a direct comparison identified no differentially expressed miRNAs between MAB-R- and MAB-S-infected cells. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes. THP-1-derived macrophages were infected in parallel with the MAB-R and MAB-S morphotypes. Poly-A selected RNAs were purified and sequenced at 1, 4 and 24 hours post-infection, and compared with uninfected controls.
2015-09-09 | E-GEOD-72821 | biostudies-arrayexpress
Project description:Mycobacterium abscessus is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB-S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R. We sampled the small RNA (sRNA) transcriptome of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 hours post-infection (hpi) using RNA-seq. MAB-S elicited a more robust transcriptional response at the miRNA level, reflecting higher cytokine levels in culture supernatants. However, and a direct comparison identified no differentially expressed miRNAs between MAB-R- and MAB-S-infected cells. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes.
2015-09-09 | GSE72769 | GEO
Project description:Bronchial Epithelial cells were exposed to microparticles generated from mycobacterium abscessus MAB cell wall per an in-house protocol. Control group was exposed to saline. Differentially expressed genes related to MAB cell wall particles were determined.
2020-08-16 | GSE140437 | GEO
Project description:Mycobacterium abscessus is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB-S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R. We sampled the small RNA (sRNA) transcriptome of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 hours post-infection (hpi) using RNA-seq. MAB-S elicited a more robust transcriptional response at the miRNA level, reflecting higher cytokine levels in culture supernatants. However, and a direct comparison identified no differentially expressed miRNAs between MAB-R- and MAB-S-infected cells. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes. THP-1-derived macrophages were infected in parallel with the MAB-R and MAB-S morphotypes. Size-selected small RNAs were purified and sequenced at 1, 4 and 24 hours post-infection, and compared with uninfected controls.
2015-09-09 | E-GEOD-72769 | biostudies-arrayexpress
Project description:The initial interactions between a host cell and a pathogen can dictate disease outcomes and are important targets for host-directed therapies. Mycobacterium abscessus (Mab) is a highly antibiotic resistant, rapidly growing non-tuberculous mycobacterium that infects patients with chronic lung diseases, like cystic fibrosis. Mab can infect host immune cells, such as macrophages, which contribute to its pathogenesis. However, our understanding of host genes that modulate the initial host-Mab interactions remains unclear. Here, we developed a functional genetic approach by coupling a Mab fluorescent reporter with a genome-wide knockout library in murine macrophages. We used this approach to conduct a forward genetic screen to uncover host genes that contribute to the uptake of Mab by macrophages. We identified known regulators of phagocytosis, such as the integrin Itgb2, and uncovered a key requirement for glycosaminoglycan (sGAG) synthesis for macrophages to efficiently bind to Mab. CRISPR-Cas9 targeting of three key sGAG biosynthesis regulators, UGDH, B4GALT7 and B3GAT3 resulted in reduced uptake of both smooth and rough Mab variants by macrophages. Mechanistic studies suggest that sGAGs function upstream of pathogen engulfment and are required for uptake of Mab but not Escherichia coli or latex beads. Further investigation found that the loss of sGAGs reduces the surface expression, but not the mRNA expression, of key integrins, suggesting a key role for sGAGs in modulating surface receptor availability. Together these studies globally defined and characterized important regulators of macrophage-Mab interactions and are a first step better understand important host genes that contribute to Mab pathogenesis and disease.
2023-01-13 | GSE221413 | GEO