Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

An immunocompetent human iPSC-derived multicellular Alveolus-on-Chip reveals early pathological events of M. tuberculosis infection

ABSTRACT: Immunocompetent and experimentally accessible alveolar systems to study human respiratory diseases are lacking. Here, we combined cells derived from a single induced pluripotent stem cell (iPSC) source with microfluidic devices that mimic lung 3D mechanical stretching and air-liquid interface. This single donor iPSC-derived Lung-on-Chip (iLoC) combines four alveolar cell types, including alveolar epithelial cells Type II and I, vascular endothelial cells, and macrophages. A combination of imaging and scRNA-seq analysis revealed that the iLoC recapitulated cellular profiles of distal lung cells present in the human lung including a range of AT2-to-AT1 cellular states and alveolar macrophages. We show that the presence of an endothelial barrier in the iLoC impacted tissue immunity in both the epithelium and macrophages. Different from 2D cellular models, infection of iLoC with the human pathogen Mycobacterium tuberculosis (Mtb) showed that both infected macrophages and epithelial cells were infected but not permissive to bacterial replication. Stochastically, large macrophage clusters containing necrotic core-like structure and Mtb replication were observed. Building a genetically engineered autophagy deficient iLoC (GE-iLoC), we found that after Mtb infection, macrophage cell death was elevated upon ATG14 deficiency with a reduced endothelial barrier integrity. Altogether, we report the first of its kind genetically tractable human alveolar model to study infections in human distal lungs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252601 | GEO | 2025/11/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Metabolic transcriptional profile of virulent Mtb-infected human AM

Project description:Mycobacterium tuberculosis (Mtb)-induced shifts in macrophage metabolism are an accepted central infection paradigm. Mtb-infected murine lung tissue exhibits gene expression changes consistent with classic Warburg metabolism and Mtb-infected murine macrophages undergo TCA cycle remodeling. Human macrophages also respond energetically to Mtb infection, however, interestingly the phenotypic nature of this response appears to vary depending on the viability of infection. Despite the overwhelming consensus that metabolic changes are critical to the host response to infection, we have little understanding of the metabolic transcriptional landscape of virulent Mtb-infected human alveolar macrophages (AM), the sentinel pulmonary immune cell during Mtb infection. Further still, whether the human AM undergoes glycolytic reprogramming and TCA cycle remodeling during virulent Mtb infection remains undefined; as is suggested to occur in circulating Mtb-infected human macrophages. Here, we aimed to characterise the metabolic transcriptional profile of virulent Mtb-infected human AM. We hypothesised that infection would induce the transcriptome of Warburg metabolism (characterised by aerobic glycolysis), TCA cycle remodeling, and reduce expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS).

2025-05-15 | GSE266414 | GEO

Multifaceted dysfunction of infant airway macrophages in response to Mycobacterium tuberculosis

Project description:Infants are vulnerable to disseminated forms of tuberculosis and suffer disproportionately high morbidity and mortality, but the reasons for this are unknown. We hypothesized that since alveolar macrophages (AMs) are critical in the uptake and containment of Mycobacterium tuberculosis (Mtb) in the lung, their function may be impaired in early life. We developed a method of obtaining AMs during rigid bronchoscopy of healthy infants with suspected airway abnormality. RNAseq analysis of Mtb-stimulated AMs from 4 infants and 4 adults was performed.

2020-03-12 | E-MTAB-7679 | biostudies-arrayexpress

Mycobacterium tuberculosis induced interferon pathways distinguish responses of Human Alveolar Macrophages from Monocyte-Derived Macrophages

Project description:Alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) mediate early lung immune responses to Mycobacterium tuberculosis (Mtb). Using paired human AMs and MDMs from 6 healthy volunteers, we investigated transcriptional profiles in responses to Mtb. We found 681 genes that were Mtb-dependent in AMs compared to MDMs, 107 that were induced in both cell types but in different directions, and 4538 that were Mtb-dependent in MDMs but not AMs (FDR < 0.05). We found that IFNA Response and IFNG Response were the top two gene sets selectively induced in Mtb-infected AM. Thus, a second experiment utilized MDMs treated with IFNA1, IFNA8, IFNE, or IFNL1 found that IFNA8 modulated Mtb-induced pro-inflammatory cytokines and, compared to other interferons,stimulated unique transcriptional profiles.

2024-03-20 | GSE236156 | GEO

Human alveolar and splenic macrophage populations display a disctinct transcriptomic response to infection with Mycobacterium tuberculosis

Project description:Mycobacterium tuberculosis (Mtb) infects alveolar macrophages (AMs) causing pulmonary tuberculosis (PTB), the more frequent form of the disease. Less frequently, Mtb disseminates to many other organs and tissues resulting in different extrapulmonary forms of TB. Nevertheless, very few studies have addressed the global mRNA response of human AMs, in particular from humans with the active form of the disease. Strikingly, almost no studies have addressed the response to infection with Mtb by human extrapulmonary macrophages.

2020-05-12 | GSE139825 | GEO

The global transcriptional profile of Mycobacterium tuberculosis during human macrophages infection

Project description:During lung infection Mycobacterium tuberculosis (Mtb) resides in macrophages and subverts the bactericidal mechanisms of these professional phagocytes. In this work we have analyzed by DNA microarray technique the global transcription profile of Mtb infecting primary human macrophages in order to identify putative bacterial pathogenic factors that can be relevant for the intracellular survival of Mtb. Keywords: time course We compared the global gene expression of the H37Rv strain of Mtb after 4 hours and 24 hours of infection of human macrophage-like THP-1 cells with the gene expression profile of the strain growing exponentially in broth cultures.

2010-05-27 | E-GEOD-6209 | biostudies-arrayexpress

Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection

Project description:Mycobacterium tuberculosis (Mtb) infects multiple lung myeloid cell subsets and persists despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination by these subsets are not fully understood. Here, we determined that four weeks post infection, after development of adaptive immune responses, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Bulk RNA-seq analysis for these subsets identified that lysosome biogenesis pathway is underexpressed in MNC1. Functional assays confirmed that Mtb-permissive MNC1 are deficient in lysosome content, lysosomal acidification, and lysosomal activity compared to AM, and have less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not alter lysosome deficiency in MNC1. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these subsets, which depend on Mtb ESX-1 secretion system. Furthermore, nilotinib-mediated TFEB activation enhances lysosome function of primary macrophages in vitro, and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor monocyte-derived lung cells for persistence; targeting lysosome biogenesis may be an effective approach to host-directed therapy for tuberculosis, enabling permissive lung cells to restrict and kill Mtb through autophagy and other mechanisms.

2023-02-08 | GSE220147 | GEO

Ontogeny of alveolar macrophages is a critical determinant of function during lung fibrosis [RNA-seq]

Project description:Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

2017-06-25 | GSE82158 | GEO

Parenteral BCG vaccine induces respiratory mucosal-resident memory macrophages and trained innate immunity via the gut-lung axis II

Project description:Besides centrally induced innate immune memory/trained immunity in the bone marrow/peripheral blood by parenteral vaccination or infection, recently emerging evidence suggests that the barrier mucosal tissue-resident innate immune memory may develop via a local inflammatory pathway following mucosal immunologic exposure. However, it remains unclear whether the mucosal-resident innate immune memory may result from integrating distally generated immunological signals following parenteral vaccination/infection. We show here that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination is able to induce memory alveolar macrophages (AM) and trained immunity at the respiratory barrier mucosa. Although parenteral BCG vaccine can centrally train bone marrow progenitors and circulating monocytes, induction of memory AM is entirely independent of circulating monocytes. Rather, parenteral BCG vaccination, via distal mycobacterial dissemination, causes a time-dependent alteration in gut microbiome, barrier function and microbial metabolites including short-chain fatty acids, and subsequently the changes in circulating and lung tissue metabolites, leading to induction of tissue-resident memory macrophages and trained innate immunity in the lung. Our study thus reveals a novel gut microbiota-mediated pathway for innate immune memory development at distal barrier mucosal tissues. Our findings have far-reaching implications in developing next-generation parenteral vaccine strategies against respiratory pathogens such as M.tb.

2022-09-16 | GSE213342 | GEO

Parenteral BCG vaccine induces respiratory mucosal-resident memory macrophages and trained innate immunity via the gut-lung axis I

2022-09-16 | GSE213340 | GEO

Molecular mechanism of interaction between IL1B + alveolar resident macrophages and pulmonary endothelial cells in sepsis induced lung injury based on single-cell RNA seq

Project description:Sepsis is a serious systemic inflammatory reaction, which often leads to acute lung injury, and then affects lung function. This study aimed to explore the molecular mechanism of the interaction between il1b+ alveolar resident macrophages and pulmonary endothelial cells during sepsis induced lung injury using single-cell RNA sequencing technology.

| PXD062802 |

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data