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 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 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.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

scholarly journals POS0611 THE EFFECT OF RITUXIMAB BIOSIMILAR THERAPY ON THE EXPRESSION OF INTERFERON-STIMULATED GENES (“INTERFERON SIGNATURE”) IN PATIENTS WITH RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 542.2-542
Author(s):  
A. Avdeeva ◽  
E. Tchetina ◽  
G. Markova ◽  
E. Nasonov
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Signature ◽  
Response To Therapy ◽  
Type I Interferons ◽  
Control Group ◽  
Type I ◽  
Acute Phase Reactants ◽  
Interferon Signature ◽  
Interferon Stimulated Genes ◽  
Healthy Donors

Background:Type I interferons (IFN-Is) are a group of molecules with pleiotropic effects on the immune system forming a crucial link between innate and adaptive immune responses. The type I interferon pathway has been implicated in the pathogenesis of a number of rheumatic diseases, including rheumatoid arthritis. IFN activity is usually quantified using expression of interferon-stimulated genes (ISGs) referred to as an IFN signature. Acellbia (BIOCAD) is the first Russian rituximab (RTX) biosimilar which was approved for medical use in rheumatoid arthritis (RA) patients in Russia and some CIS countries.Objectives:To evaluate the changes in expression of ISGs in patients (pts) with RA during RTX biosimilar therapyMethods:20 RA pts (18 woman, Me;IQR age 61.5(54-66.5) years, disease duration 39.5(20-84) months, mean DAS 28 5.6(4.9-6.8)) received two intravenous RTX biosimilar infusions (600 mg №2) in combination with DMARDs and glucocorticoids. Laboratory biomarkers were assessed at baseline and 24 weeks after the first infusion of RTX. 5 genes (IFI44L, MX1, IFIT 1, RSAD2, EPSTI1) were selected for evaluation of the “interferon signature” (Type I IFN gene signature – IFNGS). IFI44L and IFIT1 expression was undetectable, therefore the remaining three genes (MSX1, EPSTI1, RSAD2) were included into further analysis. IFNGS was calculated as the average expression values of the three selected genes. The control group included 20 age and gender matching healthy donors.Results:The baseline expression levels of MX1-11.48 (5.45-19.38), EPSTI1-12.83 (5.62-19.64), RSAD2-5.16 (2.73-10.4), and IFNGS-10.3 (5.18-17.12) in RA patients were significantly higher compared to healthy donors– 1,26 (0,73-1,6); 1,06 (0,81-1,48); 0,93 (0,72-1,19); 1,09 (0,92-1,42), (p<0.05, respectively). IFNGS was detected in 15 (75%) patients, and was not found in 5 (15%) patients. RTX induced reduction in disease activity, and the level of acute phase reactants (ESR, CRP) after 12 and 24 weeks of therapy, p<0.05 (fig.1). Increased RSAD 2 expression (p<0.05) and a trend to increasing IFNGS levels (p=0.06) were documented in the whole group, and also in patients with moderate treatment effects by week 24. Among patients with a good EULAR response to therapy, changes in expression were not significant (p> 0.05) (fig.1)Figure 1.Conclusion:Expression of IFN-stimulated genes was increased in RA patients compared to healthy donors. Increased RSAD2 and IFNGS expression was documented in patients with moderate effect of RTX therapy, therefore, these findings have important clinical relevance as predictors of RA clinical course which necessitates personified approach to treatment.Disclosure of Interests:None declared

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

scholarly journals A Kaposi's Sarcoma-Associated Herpesvirus Protein That Forms Inhibitory Complexes with Type I Interferon Receptor Subunits, Jak and STAT Proteins, and Blocks Interferon-Mediated Signal Transduction

2009 ◽  
Vol 83 (10) ◽  
pp. 5056-5066 ◽  
Author(s):  
Sabine A. Bisson ◽  
Anne-Laure Page ◽  
Don Ganem
Keyword(s):  
Kaposi's Sarcoma ◽  
Human Tumor ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Reading Frame ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Type I interferons (IFNs) are important mediators of innate antiviral defense and function by activating a signaling pathway through their cognate type I receptor (IFNAR). Here we report that lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) efficiently blocks type I IFN signaling and that an important effector of this blockade is the viral protein RIF, the product of open reading frame 10. RIF blocks IFN signaling by formation of inhibitory complexes that contain IFNAR subunits, the Janus kinases Jak1 and Tyk2, and the STAT2 transcription factor. Activation of both Tyk2 and Jak1 is inhibited, and abnormal recruitment of STAT2 to IFNAR1 occurs despite the decrement in Tyk2 activity. As a result of these actions, phosphorylation of both STAT2 and STAT1 is impaired, with subsequent failure of ISGF3 accumulation in the nucleus. The presence in the viral genome of potent inhibitors of type I IFN signaling, along with several viral genes that block IFN induction, highlights the importance of the IFN pathway in the control of this human tumor virus infection.

Epigenetic regulation of frog innate immunity: Discovery of frog microRNAs associated with antiviral responses and ranavirus infection using a Xenopus laevis skin epithelial-like cell line

2021 ◽  
Author(s):  
Lauren A. Todd ◽  
Maxwell P. Bui-Marinos ◽  
Barbara A. Katzenback
Keyword(s):  
Xenopus Laevis ◽  
Cell Line ◽  
Antiviral Immunity ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Frog Virus ◽  
Interferon Stimulated Genes ◽  
Antiviral Responses ◽  
Innate Antiviral Immunity

Epigenetic regulators such as microRNAs are emerging as conserved regulators of innate antiviral immunity in vertebrates, yet their roles in amphibian antiviral responses remain uncharacterized. We profiled changes in microRNA expressions in the Xenopus laevis skin epithelial–like cell line Xela DS2 in response to poly(I:C) – an analogue of double-stranded viral RNA and inducer of type I interferons – or frog virus 3 (FV3), an immunoevasive virus associated with amphibian mortality events. We sequenced small RNA libraries generated from untreated, poly(I:C)–treated, and FV3–infected cells. We detected 136 known X. laevis microRNAs and discovered 133 novel X. laevis microRNAs. Sixty–five microRNAs were differentially expressed in response to poly(I:C), many of which were predicted to target regulators of antiviral pathways such as cGAS–STING, RIG–I/MDA–5, TLR signaling, and type I interferon signaling, as well as products of these pathways (NF–κB–induced and interferon-stimulated genes). In contrast, only 49 microRNAs were altered by FV3 infection, fewer of which were predicted to interact with antiviral pathways. Interestingly, poly(I:C) treatment or FV3 infection downregulated transcripts encoding factors of the host microRNA biogenesis pathway. Our study is the first to suggest that host microRNAs regulate innate antiviral immunity in frogs, and sheds light on microRNA–mediated mechanisms of immunoevasion by FV3.

scholarly journals Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

2021 ◽  
Vol 9 ◽  
Author(s):  
Kunli Zhang ◽  
Sutian Wang ◽  
Hongchao Gou ◽  
Jianfeng Zhang ◽  
Chunling Li
Keyword(s):  
Signaling Pathway ◽  
Adenosine Monophosphate ◽  
Degradation Process ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Research Progress ◽  
Type I ◽  
Type I Ifn ◽  
Major Pathway ◽  
Sting Pathway

Innate immunity is the front-line defense against infectious microorganisms, including viruses and bacteria. Type I interferons are pleiotropic cytokines that perform antiviral, antiproliferative, and immunomodulatory functions in cells. The cGAS–STING pathway, comprising the main DNA sensor cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS) and stimulator of IFN genes (STING), is a major pathway that mediates immune reactions and is involved in the strong induction of type I IFN production, which can fight against microbial infections. Autophagy is an evolutionarily conserved degradation process that is required to maintain host health and facilitate capture and elimination of invading pathogens by the immune system. Mounting evidence indicates that autophagy plays an important role in cGAS–STING signaling pathway-mediated type I IFN production. This review briefly summarizes the research progress on how autophagy regulates the cGAS–STING pathway, regulating type I IFN production, with a particular focus on the crosstalk between autophagy and cGAS–STING signaling during infection by pathogenic microorganisms.

Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials

Lupus ◽  
2020 ◽  
Vol 29 (14) ◽  
pp. 1845-1853
Author(s):  
Jeffery Wei Heng Koh ◽  
Cheng Han Ng ◽  
Sen Hee Tay
Keyword(s):  
Systematic Review ◽  
Herpes Zoster ◽  
Lupus Erythematosus ◽  
Viral Infections ◽  
Meta Analysis ◽  
Type I Interferons ◽  
Type I ◽  
Upper Respiratory Tract ◽  
Type I Ifn ◽  
Tract Infections

Objective The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. Methods A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. Results Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88–7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. Conclusion This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.

scholarly journals STING: a master regulator in the cancer-immunity cycle

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yuanyuan Zhu ◽  
Xiang An ◽  
Xiao Zhang ◽  
Yu Qiao ◽  
Tongsen Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Negative Effects ◽  
Independent Manner ◽  
Adaptive Immune ◽  
Cancer Immunity

Abstract The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.

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