Differential Regulation of Type I and Type III Interferon Signaling

Stanifer, Megan L.; Pervolaraki, Kalliopi; Boulant, Steeve

doi:10.3390/ijms20061445

Cited by 167 publications

(165 citation statements)

References 192 publications

(268 reference statements)

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“…PRRs relevant to IAV, including Toll-like receptor 3 (TLR3), Melanoma differentiation-associated protein 5 (MDA5), and retinoic acid-inducible gene I (RIG-I), are known to be expressed under both naive and IFN-stimulated conditions in the human airway epithelium 17–20 . Upon recognition, PRRs bind to their cognate PAMPs and activate downstream signalling pathways that ultimately lead to the induction of both type I and III IFNs 21 . Notably, type III IFNs are particularly abundant at mucosal sites and play an important role in epithelial antiviral defence, whereas type I IFNs are expressed more ubiquitously in multiple host tissues 21 .…”

Section: Introductionmentioning

confidence: 99%

“…Upon recognition, PRRs bind to their cognate PAMPs and activate downstream signalling pathways that ultimately lead to the induction of both type I and III IFNs 21 . Notably, type III IFNs are particularly abundant at mucosal sites and play an important role in epithelial antiviral defence, whereas type I IFNs are expressed more ubiquitously in multiple host tissues 21 . Activation of either pathway leads to the upregulation of hundreds of IFN-stimulated genes (ISGs), as well as many pro-inflammatory cytokines and chemokines 13–16,21 .…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis

Kelly

Laloli

V’kovski

et al. 2020

Preprint

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Respiratory viruses, such as the 2009 pandemic strain of influenza A virus (IAV, H1N1pdm09), target cells found in the human respiratory epithelium. These cells, which form a pseudostratified epithelial layer along the airways, constitute the first line of defence against respiratory pathogens and play a crucial role in the host antiviral response. However, despite their key role in host defence, it remains unknown how distinct cell types in the respiratory epithelium respond to IAV infection and how these responses may contribute to IAV-induced pathogenesis and overall disease outcome. Here, we used single cell RNA-sequencing (scRNA-seq) to dissect the host response to IAV infection in its natural target cells. scRNA-seq was performed on human airway epithelial cell (hAEC) cultures infected with either wild-type pandemic IAV (WT) or with a mutant version of IAV (NS1R38A) that induced a robust innate immune response. We then characterized both the host and viral transcriptomes of more than 19,000 single cells across the 5 major cell types populating the human respiratory epithelium. For all cell types, we observed a wide spectrum of viral burden among single infected cells and a disparate host response between infected and bystander populations. Interestingly, we also identified multiple key differences in the host response to IAV among individual cell types, including high levels of pro-inflammatory cytokines and chemokines in secretory and basal cells and an important role for luminal cells in sensing and restricting incoming virus. Multiple infected cell types were shown to upregulate interferons (IFN), with type III IFNs clearly dominating the antiviral response. Transcriptional changes in genes related to cell differentiation, cell migration, and tissue repair were also identified. Strikingly, we also detected a shift in viral host cell tropism from non-ciliated cells to ciliated cells at later stages of infection and observed major changes in the cellular composition. Microscopic analysis of both WT and NS1R38A virus-infected hAECs at various stages of IAV infection revealed that the transcriptional changes we observed at 18 hpi were likely driving the downstream histopathological alterations in the airway epithelium. To our knowledge, this is the first study to provide a comprehensive analysis of the cell type-specific host antiviral response to a respiratory virus infection in its natural target cells – namely, the human respiratory epithelium.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis

Kelly

Laloli

V’kovski

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…When types I and III IFNs bind to their receptors, the intracellular receptor subunits undergo conformational changes to interact with Janus kinases (JAKs), which lead to the activation of the JAK/signal transducer and activator of transcription (STAT) pathway. The JAKs include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) [30]. The binding of both type I and type III IFNs to their respective receptor complexes leads to the phosphorylation of JAK1 and TYK2.…”

Section: Canonical Types I and Iii Ifn Signalingmentioning

confidence: 99%

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

Sung

Shin

2020

IJMS

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When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the IFNL4 genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.

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“…A recent review of type I IFN signalling discusses the complexities of canonical and alternative pathways of IFN signalling . These pathways are very briefly summarized in Figure .…”

Section: Type I Ifns and Ovsmentioning

confidence: 99%

“…Indeed, it was shown several years ago that valproate (a JAK1 inhibitor) prevented the resistance of synovial cell sarcoma cells to VSV 51. How inhibition of the type I IFN pathway might improve the outcomes of OV therapy is the focus of this section.A recent review of type I IFN signalling discusses the complexities of canonical and alternative pathways of IFN signalling 52. These pathways are very briefly summarized inFigure 1.…”

mentioning

confidence: 99%

The potential of the combined use of targeted type I interferon pathway inhibitors and oncolytic viruses to treat sarcomas

MacNeill

2019

Vet Comparative Oncology

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Replicating oncolytic viruses (OVs) are appealing, new, FDA‐approved, therapeutic options for humans with head and neck cancers and melanomas. These treatments are not yet available for veterinary patients, but recent clinical trials have shown several OVs to be safe in dogs and cats. Specific viruses being used to treat sarcomas in dogs include modified canine adenovirus 2, myxoma virus, vesicular stomatitis virus and reovirus. In cats with vaccine‐associated sarcomas, poxviruses have been injected postoperatively and a reduced rate of tumour recurrence was documented. To date, the response rates of canine and feline patients to OV therapy have been variable (as they are in people). Optimal methods of OV administration and dosing schedules continue to be evaluated. One way to improve outcomes of OV therapy in veterinary patients may be to use OVs in combination with other immunomodulatory therapies. This review discusses the potential utility of concurrent therapy with an OV and an inhibitor of the type I interferon pathway.

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Differential Regulation of Type I and Type III Interferon Signaling

Cited by 167 publications

References 192 publications

Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis

Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

The potential of the combined use of targeted type I interferon pathway inhibitors and oncolytic viruses to treat sarcomas

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