Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bacteriophage antidefense genes that neutralize TIR and STING immune responses

ABSTRACT: Programmed cell suicide of infected bacteria, known as abortive infection (Abi), serves as a central immune defense strategy to prevent the spread of bacteriophage viruses and other invasive genetic elements across a population. Many Abi systems utilize bespoke cyclic nucleotide immune messengers generated upon infection to rapidly mobilize cognate death effectors. Here, we identify a large family of bacteriophage nucleotidyltransferases (NTases) which synthesize competitor cyclic dinucleotide (CDN) ligands and inhibit NAD-depleting TIR effectors activated through a linked STING CDN sensor domain (TIR-STING). Through a functional screen of NTase-adjacent phage genes, we uncover candidate inhibitors of host TIR-STING suicide signaling. Among these, we demonstrate that a virus MazG-like nucleotide pyrophosphatase, Atd1, depletes the starvation alarmone (p)ppGpp, revealing a role for the alarmone-activated host toxin MazF as a key executioner of TIR-driven abortive infection. Phage NTases and counter-defenses like Atd1 preserve host viability to ensure virus propagation, and may be exploited as tools to modulate TIR and STING immune responses.

ORGANISM(S): Bacteriophage sp.

PROVIDER: GSE222071 | GEO | 2023/03/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance

Project description:Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING activation leading to direct cytotoxicity of many cell types in the tumor microenvironment (TME), systemic inflammation due to rapid tumor extravasation of the CDN, and immune ablation in the TME. These result in a failure to establish immunological memory. ExoSTING, an engineered extracellular vesicle (EV) exogenously loaded with CDN, enhances the potency of CDN and preferentially activates antigen presenting cells in the TME. Following intratumoral injection, exoSTING was retained within the tumor, enhanced local Th1 responses and recruitment of CD8+ T cells, and generated systemic anti-tumor immunity to the tumor. ExoSTING at therapeutically active doses did not induce systemic inflammatory cytokines, resulting in an enhanced therapeutic window. ExoSTING is a novel, differentiated therapeutic candidate that leverages the natural biology of EVs to enhance the activity of CDNs.

2021-03-13 | GSE168784 | GEO

Cyclic-Di-Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.

2013-10-10 | E-GEOD-51199 | biostudies-arrayexpress

SLC19A1 transports immunoreactive cyclic dinucleotides

Project description:The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage. Cytosolic DNA triggers immune responses by activating the cGAS/STING pathway. The binding of DNA to the cytosolic enzyme cGAMP synthase (cGAS), activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic[G(2’,5’)pA(3’,5’)] (2’3’-cGAMP). 2’3’-cGAMP, a cyclic dinucleotide (CDN), activates the protein ‘stimulator of interferon genes’ (STING), which in turn activates the transcription factors IRF3 and NF-κB promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2’3’-cGAMP produced by malignant cells and other CDNs, including CDNs produced by bacteria and synthetic CDNs used in cancer immunotherapy, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR interference screen to identify the reduced folate carrier SLC19A1, a folate-organic phosphate antiporter, as the major transporter for CDNs. CDN uptake and functional responses are inhibited by depleting SLC19A1 from human cells and enhanced by overexpressing SLC19A1. In both human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates, as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer, host responsiveness to CDN-producing pathogenic microorganisms, and potentially in certain inflammatory diseases.

2019-09-01 | GSE134371 | GEO

Bacteriophage antidefense genes that neutralize TIR and STING immune responses

Project description:Bacteriophage antidefense genes that neutralize TIR and STING immune responses

| PRJNA917585 | ENA

Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion

Project description:Malignant pleural effusion (MPE) is indicative of terminal malignancy with uniformly fatal prognosis. Often, two distinct compartments of tumor microenvironment, the effusion and disseminated pleural tumors, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumor associated myeloid cells with the tumor-promoting phenotype, impairing antitumor immunity. Here, we developed liposomal cyclic dinucleotide (LNP-CDN) for targeted activation of STING signaling in macrophages and dendritic cells and showed that, upon intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both the effusion and pleural tumors. Moreover, combination immunotherapy with blockade of PD-L1 potently reduced MPE volume and inhibited tumor growth not only in pleural cavity but also in lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.

2021-09-21 | GSE179783 | GEO

Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion

2021-09-21 | GSE164487 | GEO

Cyclic-Di-Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

2013-10-10 | GSE51199 | GEO

Type I IFN and not TNF, is essential for cyclic di-nucleotide-elicited CTL by a cytosolic cross-presentation pathway

Project description:Dendritic cells are the initiators of the adaptive immune response, therefore its gene expression allow us to predict the responses to vaccination. We used bone marrow derived dendritic cells (BMDC) to analyze the gene expression that result from the exposure to adjuvants. We use model antigen OVA and cyclic di-AMP (CDA) as an adjuvant in order to characterize the genes involved in the activation of dendritic cells by CDA alone or when the antigen is present. Cyclic di-nucleotides (CDN) are potent stimulators of innate and adaptive immune responses. Cyclic di-AMP (CDA) is a promising adjuvant that generates humoral and cellular immunity. The strong STING-dependent stimulation of type I IFN represents a key feature of CDA. However, recent studies suggested that this is dispensable for adjuvanticity. Here we demonstrate that stimulation of IFN-γ-secreting CD8+ cytotoxic T lymphocytes (CTL) is significantly decreased after vaccination in the absence of type I IFN signaling. The biological significance of this CTL response was confirmed by the stimulation of MHC class I-restricted protection against influenza virus challenge. We show here that type I IFN (and not TNF-α) is essential for CDA-mediated cross-presentation by a cathepsin independent, TAP and proteosome dependent cytosolic antigen processing pathway, which promotes effective cross-priming and further CTL induction. Our data clearly demonstrate that type I IFN signaling is critical for CDN-mediated cross-presentation

2017-07-15 | GSE101466 | GEO

Comparative analysis of gut bacteriophage between older and young people

Project description:Given the gut microbiota involve aging processing, we performed comparative analysis of gut bacteriophage between older and young subjects using next-generation sequencing (NGS). In our previous study, we found that the Ruminococcaceae is higher in aged subjects comparing to young one. To identify the bacteriophage targeting to the Ruminococcaceae, we also access the composition of phage in the Ruminococcaceae (ATCC, TSD-27) after incubated with human stool samples. The Lactobacillus (ATCC, LGG) targeting phage was used as the control. The virome sequencing analysis using NGS indicated that Myoviridae are high enrich in young subjects and predominate in TSD-27 targeting phage.

2022-07-20 | GSE196622 | GEO

Whole transcriptome sequencing of phage φR1-37 and its host Yersinia enterocolitica

Project description:RNA-sequencing was preformed from RNA isolated from bacteria infected with the bacteriophage. In order to reveal the phage-host interactions between φR1-37 and Yersinia enterocolitica throughout the phage infection cycle, both the transcriptomes were scrutinized during all the stages of infection.

2016-01-22 | GSE77068 | GEO

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