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Broad transcriptional firing represses bactericidal activity in human airway neutrophils

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167070 | GEO | 2021/02/19

REPOSITORIES: GEO

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BROAD TRANSCRIPTIONAL FIRING REPRESSES BACTERICIDAL ACTIVITY IN HUMAN AIRWAY NEUTROPHILS

Project description:Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacteria infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of survival and anabolic genes, and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Remarkably, treatment by the RNA polymerase II and III inhibitor alpha-amanitin restored expression of key antimicrobial genes, and increased bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the terminal organ via RNA and protein synthesis, leading to adaptations that profoundly impact their canonical functions (i.e., bacterial clearance).

2021-01-22 | GSE165265 | GEO

Broad transcriptional firing represses bactericidal activity in human airway neutrophils [10hours_transmigrated_CFASN_Neutrophils]

Project description:In this model, naïve blood neutrophils are migrated through a small airway epithelium grown at air-liquid interface toward CF airway fluid supernatant (CFASN, which corresponds to sputum sequentially centrifuged to remove cells and bacteria) or leukotriene B4 (LTB4, transmigration control), placed apically.

2021-02-19 | GSE167069 | GEO

Broad transcriptional firing represses bactericidal activity in human airway neutrophils [Transcriptional_Blockage_CFASN_Neutrophils]

Project description:Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacteria infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of survival and anabolic genes, and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Remarkably, treatment by the RNA polymerase II and III inhibitor Alpha-amanitin restored expression of key antimicrobial genes, and increased bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the terminal organ via RNA and protein synthesis, leading to adaptations that profoundly impact their canonical functions (i.e., bacterial clearance).

2021-02-19 | GSE167066 | GEO

Transcriptional firing represses bactericidal activity in cystic fibrosis airway neutrophils.

Project description:Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacterial infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of anabolic genes and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Treatment by the RNA polymerase II and III inhibitor α-amanitin restores the expression of key antimicrobial genes and increases the bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the site of inflammation via RNA and protein synthesis, leading to adaptations that affect their canonical functions (i.e., bacterial clearance).

| S-EPMC8080108 | biostudies-literature

Broad transcriptional firing represses bactericidal activity in human airway neutrophils

Project description:Broad transcriptional firing represses bactericidal activity in human airway neutrophils

| PRJNA702818 | ENA

BROAD TRANSCRIPTIONAL FIRING REPRESSES BACTERICIDAL ACTIVITY IN HUMAN AIRWAY NEUTROPHILS

Project description:BROAD TRANSCRIPTIONAL FIRING REPRESSES BACTERICIDAL ACTIVITY IN HUMAN AIRWAY NEUTROPHILS

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Broad transcriptional firing represses bactericidal activity in human airway neutrophils [10hours_transmigrated_CFASN_Neutrophils]

Project description:Broad transcriptional firing represses bactericidal activity in human airway neutrophils [10hours_transmigrated_CFASN_Neutrophils]

| PRJNA702819 | ENA

Broad transcriptional firing represses bactericidal activity in human airway neutrophils [Transcriptional_Blockage_CFASN_Neutrophils]

Project description:Broad transcriptional firing represses bactericidal activity in human airway neutrophils [Transcriptional_Blockage_CFASN_Neutrophils]

| PRJNA702815 | ENA

Diphenyleneiodonium chloride (DPIC) displays broad-spectrum bactericidal activity.

Project description:Indiscriminate use of antibiotics globally has lead to an increase in emergence of drug-resistant pathogens under both nosocomial, as well as more worryingly, in community setting as well. Further, a decrease in the corporate interest and financial commitment has exerted increasing pressure on a rapidly dwindling antimicrobial drug discovery and developmental program. In this context, we have screened the Library of Pharmacologically Active Compounds (LOPAC, Sigma) against Staphylococcus aureus and Mycobacterium tuberculosis to identify potent novel antimicrobial molecules amongst non-antibiotic molecules. Microplate-based whole cell growth assay was performed to analyze the antimicrobial potency of the compounds against Staphylococcus aureus and Mycobacterium tuberculosis. We identified diphenyleneiodonium chloride, a potent inhibitor of NADH/NADPH oxidase, as a broad-spectrum antibiotic potently active against drug resistant strains of Staphylococcus aureus and Mycobacterium tuberculosis. Intriguingly, the diphenyleneiodonium chloride was also very effective against slow-growing non-replicating Mtb persisters. FIC index demonstrated a strongly synergistic interaction between diphenyleneiodonium chloride and Rifampicin while it did not interact with INH. The antimicrobial property of the diphenyleneiodonium chloride was further validated in vivo murine neutropenic thigh S. aureus infection model. Taken together, these findings suggest that Diphenyleneiodonium chloride can be potentially repurposed for the treatment of tuberculosis and staphylococcal infections.

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A Transcriptomic Reporter Assay Employing Neutrophils to Measure Immunogenic Activity of Septic Patients' Plasma

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-03-17 | E-GEOD-49758 | biostudies-arrayexpress