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Integrated genomics of Crohn’s disease risk variant identifies a role for CLEC12A in antibacterial autophagy

ABSTRACT: Using integrated genomics we identify a role for CLEC12A in antibacterial autophagy. Clec12a-/- mice are more susceptible to bacterial infection and CLEC12A deficient cells exhibit impaired antibacterial autophagy. We used transcriptional profilinf to understand the role of CLEC12A in the response to Salmonella and Listeria.

ORGANISM(S): Mus musculus

PROVIDER: GSE69132 | GEO | 2015/06/30

SECONDARY ACCESSION(S): PRJNA284662

REPOSITORIES: GEO

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Integrated genomics of Crohn’s disease risk variant identifies a role for CLEC12A in antibacterial autophagy

Project description:Using integrated genomics we identify a role for CLEC12A in antibacterial autophagy. Clec12a-/- mice are more susceptible to bacterial infection and CLEC12A deficient cells exhibit impaired antibacterial autophagy. We used transcriptional profilinf to understand the role of CLEC12A in the response to Salmonella and Listeria. Bone marrow-derived macrophages from WT or Clec12a-/- mice were infected with Salmonella enterica serovar Typhimurium or Listeria monocytogenes. Cells were harvested at 0,3,6, and 24hours post-infection for RNA analysis. Please note that single-end sequencing was performed but two files: R1 files that contained the sample barcodes (19 or 17bp reads) and R2 files that contained the single-end-sequenced 46bp cDNA reads were generated. Since the barcode info is mostly redundant, only R2 reads were submitted (described in 'raw_file_readme.txt').

2015-06-30 | E-GEOD-69132 | biostudies-arrayexpress

CD44a functions as a regulator of p53 signaling, apoptosis and autophagy in the antibacterial immune response

Project description:CD44 is a transmembrane adhesion molecule and the major receptor for hyaluronan. The function of CD44 has been implicated in numerous biological processes. Our study finds that zebrafish CD44a variants function as positive regulators in antibacterial response. In order to reveal the possible antibacterial mechanism of CD44a, the wild-type and CD44a-/--14del zebrafish larvaes infected with E. piscicida collected at 24 and 48 hpi were used for transcriptome sequencing. Our data demonstrate that zebrafish CD44a functions as a regulator of p53 signaling, apoptosis and autophagy in the antibacterial immune response.

2021-07-26 | GSE180770 | GEO

Scheidel2016 - In Silico Knockout Studies of Xenophagy Capturing of Salmonella

Project description:Xenophagy, also known as antibacterial autophagy, is a process of capturing and eliminating cytosolic pathogens, like Salmonella. Salmonella is the best-studied model organism for xenophagy. We present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data and contains all known processes of Salmonella xenophagy in epithelial. The model comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. The Petri net is connected, covered by T-invariants, and each T-invariant has a meaningful biological interpretation. We checked the model structure for consistencies and correctness. We found 16 basic functional modules, which describe different pathways of the autophagic capturing of Salmonella and reflect the basic dynamics of the system. The PN model of Salmonella xenophagy comprises 61 places, including nine logical places, and 69 transitions connected by 184 arcs.

2020-04-09 | MODEL1904150001 | BioModels

In-vitro evaluation of Pseudomonas fluorescens antibacterial activity against Listeria spp. isolated from New Zealand horticultural environments

Project description:Beneficial bacteria with antibacterial properties are an attractive alternative to chemical-based antibacterial or bactericidal agents. The aim of our study was to source such bacteria from horticultural produce and environments and to explore the mechanisms of their antimicrobial properties. Four strains of Pseudomonas fluorescens were isolated that possessed antibacterial activity against the pathogen Listeria monocytogenes.

2023-03-10 | PXD019965 | Pride

Integrated Genomics of Crohn's Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy.

Project description:The polymorphism ATG16L1 T300A, associated with increased risk of Crohn's disease, impairs pathogen defense mechanisms including selective autophagy, but specific pathway interactions altered by the risk allele remain unknown. Here, we use perturbational profiling of human peripheral blood cells to reveal that CLEC12A is regulated in an ATG16L1-T300A-dependent manner. Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1(∗)300A risk allele. Clec12a(-/-) mice are more susceptible to Salmonella infection, supporting a role for CLEC12A in antibacterial defense pathways in vivo. CLEC12A is recruited to sites of bacterial entry, bacteria-autophagosome complexes, and sites of sterile membrane damage. Integrated genomics identified a functional interaction between CLEC12A and an E3-ubiquitin ligase complex that functions in antibacterial autophagy. These data identify CLEC12A as early adaptor molecule for antibacterial autophagy and highlight perturbational profiling as a method to elucidate defense pathways in complex genetic disease.

| S-EPMC4507440 | biostudies-literature

Mus musculus

Project description:Integrated genomics of Crohn’s disease risk variant identifies a role for CLEC12A in antibacterial autophagy

| PRJNA284662 | ENA

CD44a functions as a regulator of p53 signaling, apoptosis and autophagy in the antibacterial immune response

Project description:CD44a functions as a regulator of p53 signaling, apoptosis and autophagy in the antibacterial immune response

| PRJNA749459 | ENA

Aeromonas spp. antibacterial resistance

Project description:Aeromonas spp. antibacterial resistance

| PRJEB65842 | ENA

Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity

Project description:Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity in vivo and in vitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in murine hepatocytes. These findings identify SLC13A3 as a key itaconate importer in murine hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.

2024-07-08 | GSE230735 | GEO

An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity.

Project description:Type I interferons were discovered as the primary antiviral cytokines and are now known to serve critical functions in host defense against bacterial pathogens. Accordingly, established mediators of interferon antiviral activity may mediate previously unrecognized antibacterial functions. RNase-L is the terminal component of an RNA decay pathway that is an important mediator of interferon-induced antiviral activity. Here we identify a novel role for RNase-L in the host antibacterial response. RNase-L-/- mice exhibited a dramatic increase in mortality following challenge with Bacillus anthracis and Escherichia coli; this increased susceptibility was due to a compromised immune response resulting in increased bacterial load. Investigation of the mechanisms of RNase-L antibacterial activity indicated that RNase-L is required for the optimal induction of proinflammatory cytokines that play essential roles in host defense from bacterial pathogens. RNase-L also regulated the expression of the endolysosomal protease, cathepsin-E, and endosome-associated activities, that function to eliminate internalized bacteria and may contribute to RNase-L antimicrobial action. Our results reveal a unique role for RNase-L in the antibacterial response that is mediated through multiple mechanisms. As a regulator of fundamental components of the innate immune response, RNase-L represents a viable therapeutic target to augment host defense against diverse microbial pathogens. two strains: wildtype and knockout, three time points: untreated, 2hours, and 8hours. three replication for each group. Totally 18 samples.

2008-12-19 | E-GEOD-13530 | biostudies-arrayexpress

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