scholarly journals The opportunistic intracellular bacterial pathogen Rhodococcusequi elicits type I interferon by engaging cytosolic DNA sensing in macrophages

2021 ◽  
Vol 17 (9) ◽  
pp. e1009888
Author(s):  
Krystal J. Vail ◽  
Bibiana Petri da Silveira ◽  
Samantha L. Bell ◽  
Noah D. Cohen ◽  
Angela I. Bordin ◽  
...  
Keyword(s):  
Bacterial Pathogen ◽  
Opportunistic Pathogen ◽  
Type I ◽  
Type I Ifn ◽  
Dna Sensing ◽  
Interferon Stimulated Genes ◽  
Galectin 3 ◽  
Dna Release ◽  
Phagosomal Membrane ◽  
Expression Program

Rhodococcusequi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi, little is known about how intracellularR. equi is sensed by macrophages. Here, we discovered that that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnband interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA sensing pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this, we found that a population of ~12% of R. equi phagosomes recruits the galectin-3,-8 and -9 danger receptors. Interestingly, neither phagosomal damage nor induction of type I IFN require the R. equi’s virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulates ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.

scholarly journals The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferons by engaging cytosolic DNA sensing in macrophages

2021 ◽  
Author(s):  
Krystal J Vail ◽  
Bibiana Petri da Silveira ◽  
Samantha L Bell ◽  
Angela I Bordin ◽  
Noah D Cohen ◽  
...  
Keyword(s):  
Bacterial Pathogen ◽  
Opportunistic Pathogen ◽  
Rhodococcus Equi ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Dna Sensing ◽  
Interferon Stimulated Genes ◽  
Galectin 3 ◽  
Dna Release

Rhodococcus equi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi, little is known about how intracellular R. equi is sensed by macrophages. Here, we discovered that that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnb and interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics, demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA surveillance pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this we found that a population of ~12% of R. equi phagosomes recruited the galectin-3, -8 and -9 danger receptors. Interesting, neither phagosomal damage nor induction of type I IFN required the R. equi's virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulated ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.

scholarly journals Spontaneous Type I IFN response in SAMHD1-deficient mice requires both, functional intracellular RNA and DNA sensing pathways

2015 ◽  
Vol 13 (S1) ◽  
Author(s):  
R Behrendt ◽  
T Schumann ◽  
A Gerbaulet ◽  
S Wittmann ◽  
T Gramberg ◽  
...  
Keyword(s):  
Type I ◽  
Type I Ifn ◽  
Dna Sensing ◽  
Deficient Mice ◽  
Rna And Dna

scholarly journals Modified Vaccinia Virus Ankara Triggers Type I IFN Production in Murine Conventional Dendritic Cells via a cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway

2014 ◽  
Vol 10 (4) ◽  
pp. e1003989 ◽  
Author(s):  
Peihong Dai ◽  
Weiyi Wang ◽  
Hua Cao ◽  
Francesca Avogadri ◽  
Lianpan Dai ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Vaccinia Virus ◽  
Type I ◽  
Type I Ifn ◽  
Dna Sensing ◽  
Modified Vaccinia Virus Ankara

scholarly journals A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection

2020 ◽  
Author(s):  
Tania J. Lebratti ◽  
Ying Shiang Lim ◽  
Adjoa Cofie ◽  
Prabhakar S. Andey ◽  
Xiaoping Jiang ◽  
...  
Keyword(s):  
Type I ◽  
Sequencing Analysis ◽  
Type I Ifn ◽  
Therapeutic Blockade ◽  
Interferon Stimulated Genes ◽  
Neutrophil Depletion ◽  
Genetic Deletion ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Genital Disease

ABSTRACTNeutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/β receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I IFN signaling is a driver of pathogenic neutrophil responses, and identifies IL-18 as a novel component of disease during genital HSV-2 infection.

scholarly journals Bluetongue Virus NS4 Protein Is an Interferon Antagonist and a Determinant of Virus Virulence

2016 ◽  
Vol 90 (11) ◽  
pp. 5427-5439 ◽  
Author(s):  
Maxime Ratinier ◽  
Andrew E. Shaw ◽  
Gerald Barry ◽  
Quan Gu ◽  
Luigina Di Gialleonardo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Viral Replication ◽  
Bluetongue Virus ◽  
Animal Species ◽  
Nonstructural Protein ◽  
Type I ◽  
Mrna Levels ◽  
Type I Ifn ◽  
Interferon Stimulated Genes ◽  
Viral Virulence

ABSTRACTBluetongue virus (BTV) is the causative agent of bluetongue, a major infectious disease of ruminants with serious consequences to both animal health and the economy. The clinical outcome of BTV infection is highly variable and dependent on a variety of factors related to both the virus and the host. In this study, we show that the BTV nonstructural protein NS4 favors viral replication in sheep, the animal species most affected by bluetongue. In addition, NS4 confers a replication advantage on the virus in interferon (IFN)-competent primary sheep endothelial cells and immortalized cell lines. We determined that in cells infected with an NS4 deletion mutant (BTV8ΔNS4), there is increased synthesis of type I IFN compared to cells infected with wild-type BTV-8. In addition, using RNA sequencing (RNA-seq), we show that NS4 modulates the host IFN response and downregulates mRNA levels of type I IFN and interferon-stimulated genes. Moreover, using reporter assays and protein synthesis assays, we show that NS4 downregulates the activities of a variety of promoters, such as the cytomegalovirus immediate-early promoter, the IFN-β promoter, and a promoter containing interferon-stimulated response elements (ISRE). We also show that the NS4 inhibitory activity on gene expression is related to its nucleolar localization. Furthermore, NS4 does not affect mRNA splicing or cellular translation. The data obtained in this study strongly suggest that BTV NS4 is an IFN antagonist and a key determinant of viral virulence.IMPORTANCEBluetongue is one of the main infectious diseases of ruminants and is caused by bluetongue virus (BTV), an arthropod-borne virus transmitted from infected to susceptible animals byCulicoidesbiting midges. Bluetongue has a variable clinical outcome that can be related to both virus and host factors. It is therefore critical to understand the interplay between BTV and the host immune responses. In this study, we show that a nonstructural protein of BTV (NS4) is critical to counteract the innate immune response of the host. Infection of cells with a BTV mutant lacking NS4 results in increased synthesis of IFN-β and upregulation of interferon-stimulated genes. In addition, we show that NS4 is a virulence factor for BTV by favoring viral replication in sheep, the animal species most susceptible to bluetongue.

scholarly journals Interferon-Independent Upregulation of Interferon-Stimulated Genes during Human Cytomegalovirus Infection is Dependent on IRF3 Expression

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 246 ◽  
Author(s):  
Caroline Ashley ◽  
Allison Abendroth ◽  
Brian McSharry ◽  
Barry Slobedman
Keyword(s):  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Human Fibroblasts ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Interferon Stimulated Genes ◽  
Stat Signaling ◽  
Isg15 Expression

The antiviral activity of type I interferons (IFNs) is primarily mediated by interferon-stimulated genes (ISGs). Induction of ISG transcription is achieved when type I IFNs bind to their cognate receptor and activate the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Recently it has become clear that a number of viruses are capable of directly upregulating a subset of ISGs in the absence of type I IFN production. Using cells engineered to block either the response to, or production of type I IFN, the regulation of IFN-independent ISGs was examined in the context of human cytomegalovirus (HCMV) infection. Several ISGs, including IFIT1, IFIT2, IFIT3, Mx1, Mx2, CXCL10 and ISG15 were found to be upregulated transcriptionally following HCMV infection independently of type I IFN-initiated JAK-STAT signaling, but dependent on intact IRF3 signaling. ISG15 protein regulation mirrored that of its transcript with IFNβ neutralization failing to completely inhibit ISG15 expression post HCMV infection. In addition, no detectable ISG15 protein expression was observed following HCMV infection in IRF3 knockdown CRISPR/Cas-9 clones indicating that IFN-independent control of ISG expression during HCMV infection of human fibroblasts is absolutely dependent on IRF3 expression.

scholarly journals Streptococcus pneumoniae DNA Initiates Type I Interferon Signaling in the Respiratory Tract

mBio ◽  
2011 ◽  
Vol 2 (3) ◽  
Author(s):  
Dane Parker ◽  
Francis J. Martin ◽  
Grace Soong ◽  
Bryan S. Harfenist ◽  
Jorge L. Aguilar ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Type I Interferon ◽  
Bacterial Pathogen ◽  
Central Component ◽  
Type I ◽  
Respiratory Pathogens ◽  
Airway Epithelial ◽  
Type I Ifn ◽  
Mucosal Epithelium ◽  
Content Type

ABSTRACTThe mucosal epithelium is the initial target for respiratory pathogens of all types. While type I interferon (IFN) signaling is traditionally associated with antiviral immunity, we demonstrate that the extracellular bacterial pathogenStreptococcus pneumoniaeactivates the type I IFN cascade in airway epithelial and dendritic cells. This response is dependent upon the pore-forming toxin pneumolysin. Pneumococcal DNA activates IFN-β expression through a DAI/STING/TBK1/IRF3 cascade.Tlr4−/−,Myd88−/−,Trif−/−, andNod2−/−mutant mice had no impairment of type I IFN signaling. Induction of type I IFN signaling contributes to the eradication of pneumococcal carriage, as IFN-α/β receptor null mice had significantly increased nasal colonization withS. pneumoniaecompared with that of wild-type mice. These studies suggest that the type I IFN cascade is a central component of the mucosal response to airway bacterial pathogens and is responsive to bacterial pathogen-associated molecular patterns that are capable of accessing intracellular receptors.IMPORTANCEThe bacteriumStreptococcus pneumoniaeis a leading cause of bacterial pneumonia, leading to upwards of one million deaths a year worldwide and significant economic burden. Although it is known that antibody is critical for efficient phagocytosis, it is not known how this pathogen is sensed by the mucosal epithelium. We demonstrate that this extracellular pathogen activates mucosal signaling typically activated by viral pathogens via the pneumolysin pore to activate intracellular receptors and the type I interferon (IFN) cascade. Mice lacking the receptor to type I IFNs have a reduced ability to clearS. pneumoniae, suggesting that the type I IFN cascade is central to the mucosal clearance of this important pathogen.

scholarly journals Stage-specific ISG expression reveals functional convergence of type I and II IFNs in SIV infection

2017 ◽  
Author(s):  
Nadia Echebli ◽  
Nicolas Tchitchek ◽  
Stéphanie Dupuy ◽  
Timothée Bruel ◽  
Caroline Peireira Bittencourt Passaes ◽  
...  
Keyword(s):  
Viral Infections ◽  
Early Stage ◽  
Expression Patterns ◽  
Chronic Phase ◽  
Hiv Infections ◽  
Type I ◽  
Type Ii ◽  
Type I Ifn ◽  
Interferon Stimulated Genes ◽  
Siv Infection

AbstractInterferons play a major role in controlling viral infections including HIV/SIV infections. Persistent up-regulation of interferon-stimulated-genes (ISGs) is associated with chronic immune activation and progression in SIV/HIV infections, but the respective contribution of different IFNs is unclear. We analyzed the expression of annotated IFN-induced genes in SIV-infected macaques to decrypt the respective roles of type-I (α,β) and type-II (γ) IFNs. Both IFN types were induced in lymph nodes during early stage of primary infection. Induction of type-II IFN persisted during the chronic phase, in contrast to undetectable induction of type-I IFN. Interferome-based analysis of ISGs revealed that at both acute and chronic infection phases most differentially expressed ISGs were inducible by both type-I and type-II IFNs and displayed the highest increases, indicating strong convergence and synergy between type-I and type-II IFNs. The analysis of functional signatures of ISG expression revealed temporal changes in IFN expression patterns identifying phase-specific ISGs. These results suggest that IFN-γ strongly contribute to shape ISG upregulation in addition to type-I IFN and may contribute to progression.

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