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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE13530 | GEO | 2008/12/19

SECONDARY ACCESSION(S): PRJNA110145

REPOSITORIES: GEO

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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

Initiation of a ZAKa-dependent Ribotoxic Stress Response by the Innate Immunity Endoribonuclease RNase L

Project description:RNase L is a regulated endoribonuclease in higher vertebrates that functions in antiviral innate immunity. Interferons induce OAS enzymes that sense double-stranded RNA of viral origin leading to synthesis of 2’,5’-oligoadenylate (2-5A) activators of RNase L. However, it is unknown precisely how RNase L modulates host transcriptome through its endoribonuclease activity. To isolate effects of RNase L from other effects of double-stranded RNA or virus, 2-5A was directly introduced into cells. Here we report that RNase L activation by 2-5A causes a ribotoxic stress response that requires the ribosome-associated MAP3K, ZAK. Subsequently, the stress-activated protein kinases (SAPK) JNK and p38 are phosphorylated. RNase L activation profoundly altered the transcriptome by widespread depletion of mRNAs associated with different cellular functions, but also by SAPK-dependent induction of inflammatory genes. Our findings show that 2-5A is a ribotoxic stressor that causes RNA damage through RNase L triggering a ZAK kinase cascade leading to proinflammatory signaling and apoptosis.

2024-03-01 | GSE253530 | GEO

Mast cell cytonemes as a defense mechanism against Coxiella burnetii

Project description:Mast cells (MCs) are critical mediators of inflammation; however, their microbicidal activity against invading pathogens remains largely unknown. Here, we describe a nonpreviously reported antibacterial mechanism used by MCs against Coxiella burnetii, the agent of Q fever. We show that C. burnetii interaction with MCs does not result in bacterial uptake but rather induces the formation of extracellular actin filaments named cytonemes. MC cytonemes express cathelicidin and neutrophil elastase and mediate the capture and destruction of entrapped bacteria. We provide evidence that MC cytoneme formation and microbicidal activity are dependent on the cooperation of the scavenger receptor CD36 and Toll-like receptor 4. Taken together, our results suggest that MCs use an extracellular sophisticated mechanism of defense to eliminate intracellular pathogens, such as C. burnetii, before their entry into host cells.

2019-03-13 | GSE111971 | GEO

Type II interferon-dependent antibacterial defense in the lungs is compromised in diabetes

Project description:Diabetes mellitus is associated with an increased risk of pneumonia, which is often caused by so-called typical and atypical pathogens including Streptoccocus pneumoniae and Legionella pneumophila, respectively. Here, we employed a varity of mouse models to investigate how diabetes influences pulmonary antibacterial immunity. Following intranasal infection with Streptoccocus pneumoniae or Legionella pneumphila, type 2 diabetic and prediabetic mice had higher bacterial loads in their lungs as compared to control animals. Single cell RNA sequencing, flow cytometry, and functional analyses revealed a compromised type II IFN (IFNg) production by natural killer cells in diabetic and prediabetic mice, which was linked to reduced IL-12 production by CD103+ dendritic cells. Treatment with IFNg rescued antibacterial defense against L. pneumophila but not against S. pneumoniae in diabetic animals, although impaired production of IFNg also contributed to the compromised anti-pneumococcal resistance in diabetic mice. These findings uncover a mechanism that could help to explain why type 2 diabetes predisposes to pneumonia. We establish proof of concept for host-directed treatment strategies to reinforce compromised IFNg-mediated antibacterial defense against atypical lung pathogens.

2024-11-19 | GSE270694 | GEO

A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3

Project description:Type I interferons (IFNs) are consequential cytokines in antibacterial defense. Whether and how bacterial pathogens inhibit innate immune receptor-driven type I IFN expression remains mostly unknown. By screening a library of enterohemorrhagic Escherichia coli (EHEC) mutants, we uncovered EhaF, an uncharacterized protein, as an inhibitor of innate immune responses including IFNs. Further analyses identified EhaF as a secreted autotransporter—a type of bacterial secretion system with no known innate immune-modulatory function—that translocates into host cell cytosol and inhibit IFN response to EHEC. Mechanistically, EhaF interacts with and inhibits the MiT/TFE family transcription factor TFE3 resulting in impaired TANK phosphorylation and consequently, reduced IRF3 activation and type I IFN expression. Notably, EhaF-mediated innate immune suppression promotes EHEC colonization and pathogenesis in vivo. Overall, this study has uncovered a previously unknown autotransporter-based bacterial strategy that targets a specific transcription factor to subvert innate host defense.

2023-04-13 | PXD041070 | Pride

Activity of uncleaved caspase-8 controls anti-bacterial immune defense and TLR-induced cytokine production independent of cell death

Project description:Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense.

2016-09-15 | GSE86922 | GEO

Bacterial sepsis triggers an antiviral response that causes translation shutdown

Project description:In response to viral pathogens, the host upregulates antiviral genes that suppress translation of viral mRNAs. However, induction of such antiviral responses may not be exclusive to viruses as the pathways lie at the intersection of broad inflammatory networks that can also be induced by bacterial pathogens. Using a model of Gram-negative sepsis, we show that propagation of kidney damage initiated by a bacterial origin ultimately involves antiviral responses that result in host translation shutdown. We determined that activation of the Eif2ak2-Eif2α axis is the key mediator of translation initiation block in late phase sepsis. Reversal of this axis mitigated kidney injury. Furthermore, temporal profiling of the kidney translatome revealed that multiple genes involved in formation of the initiation complex were translationally altered during bacterial sepsis. Collectively, our findings implicate that translation shutdown is indifferent to the specific initiating pathogen and is an important determinant of tissue injury in sepsis.

2018-11-16 | GSE122274 | GEO

Bacterial sepsis triggers an antiviral response that causes translation shutdown

2018-10-06 | GSE120877 | GEO

Transcription profiling by array of E. coli NCTC 9001 challenged with four different cationic antimicrobial peptides

Project description:Obtaining an in depth understanding of the arms races between peptides comprising the innate immune response and bacterial pathogens is of fundamental interest and will inform the development of new antibacterial therapeutics. Many cationic antimicrobial peptides (AMPs) share a range of structural and physical features that have been linked to antibacterial activity and yet they vary dramatically in their potency towards the same bacterial target. We hypothesised that a whole organism view of AMP challenge on Escherichia coli could provide a sophisticated, bacterial perspective enabling understanding of how potency is linked to mode of action. We used a 1H NMR metabolomic approach to characterise the effect on E. coli of challenge with four structurally and physically related AMPs: magainin 2, pleurocidin, buforin II and a designed peptide comprising D-amino acids only. Sub-inhibitory conditions, where these peptides nevertheless induced a bacterial response, were identified enabling electron microscopic and transcriptomic analyses. Although some common features of the bacterial response to AMP challenge could be identified, the metabolomes, morphological changes and the vast majority of the changes in gene expression were specific to each AMP. We show the antibacterial mode of action of AMPs can be accurately predicted by comparing ontological profiles generated by transcriptomic analyses. The response of E. coli to AMP challenge is highly plastic, with the bacteria capable of deploying a multifaceted response adapted to the mode of action rather than the physical properties of the AMP.

2014-01-21 | E-MTAB-1703 | biostudies-arrayexpress

Transcription profiling of human innate immune responses (host response) to bacteria

Project description:The innate immune response is crucial for defense against microbial pathogens. To investigate the molecular choreography of this response, we carried out a systematic examination of the gene expression program in human peripheral blood mononuclear cells responding to bacteria and bacterial products. We found a remarkably stereotyped program of gene expression induced by bacterial lipopolysaccharide and diverse killed bacteria. An intricately choreographed expression program devoted to communication between cells was a prominent feature of the response. Other features suggested a molecular program for commitment of antigen-presenting cells to antigens captured in the context of bacterial infection. Despite the striking similarities, there were qualitative and quantitative differences in the responses to different bacteria. Modulation of this host-response program by bacterial virulence mechanisms was an important source of variation in the response to different bacteria.

2005-09-21 | E-SMDB-573 | biostudies-arrayexpress

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