Interferon-Stimulated Genes as Enhancers of Antiviral Innate Immune Signaling

Crosse, Keaton M.; Monson, Ebony A; Beard, Michael R.; Helbig, Karla J.

doi:10.1159/000484258

Cited by 153 publications

(121 citation statements)

References 50 publications

(80 reference statements)

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…Type I interferons (IFN-I) bind to IFN (IFN-α/β) receptors on the surface of NK cells to prime, activate and initiate mechanisms for the destruction of infected cells. The subsequent stimulation of the IFN signalling pathway results in the increased expression of several interferon stimulated genes (ISGs) which have direct and indirect antiviral activities (1).…”

Section: Introductionmentioning

confidence: 99%

LAG3 is a Central Regulator of NK Cell Cytokine Production

Narayanan

Ahl

Bijin

et al. 2020

Preprint

View full text Add to dashboard Cite

25Natural killer (NK) cells are innate effectors, which play a crucial role in controlling 26 viral infections. Administration of IFN-α has shown promising results as a therapeutic, 27 controlling HIV, and chronic viral hepatitis. However the downstream mechanisms by which 28 IFN-α mediates its anti-viral effects is largely unknown. In this investigation, we evaluated 29 the impact of IFN-α on peripheral blood NK cells from healthy donors. High dimensional 30 flow cytometry analysis of NK cell surface receptors following exposure to IFN-α showed an 31 increased expression of the check point inhibitor LAG3. Further characterization revealed 32 that LAG3 was expressed in a subset of NK cells with high expression of activation and 33 maturation markers. Assessment of metabolic pathways showed that LAG3+ NK cells had 34 enhanced rates of glycolysis and glycolytic capacity, suggesting that it is a primed effector 35 subset with enhanced glucose metabolism. Inhibition of LAG3 on NK cells using antibody in 36 vitro resulted in a profound increase in secretion of cytokines IFN-γ, TNF-α, MIP-1α and 37 MIP-1β, without affecting the cytotoxic activity. Taken together, these results showed that 38 LAG3 is a negative regulator of cytokine production by mature NK cells. 39 40 Introduction: 41 2 The plasmacytoid (pDC)-Natural Killer (NK) cell axis acts as a first line of defence by the 42 host against viral infections. pDCs secrete type I interferons upon recognizing virus-43 associated pathogen associated molecular patterns (PAMPs) through pattern recognition 44 receptors (PRRs). Type I interferons (IFN-I) bind to IFN (IFN-/) receptors on the surface 45 of NK cells to prime, activate and initiate mechanisms for the destruction of infected cells. 46 The subsequent stimulation of the IFN signalling pathway results in the increased expression 47 65 expression of LAG3, an inhibitory receptor, commonly associated with T cell exhaustion in 66 chronic infections and cancer. To date, the function of LAG3 in NK cells is not well 67 understood due to contrasting results from mouse and human NK cells. While studies using 68 knockout mouse models suggested a positive role for LAG3 in NK cell cytotoxicity, these 69 could not be successfully reproduced in human NK cells (10,11). High dimensional flow 70 cytometry analysis in these studies revealed that LAG3 expression marks a subset of mature 71 activated NK cells. Metabolic assays additionally showed that NK cells expressing LAG3 72 have enhanced glycolytic activity. Blockade of LAG3 enhanced cytokine production by 73 activated NK cells without altering their cytotoxicity. Taken together, these results 74 demonstrate that LAG3 is a negative regulator of cytokine production and a potential 75 therapeutic target for chronic viral infections. 76 77 78 3 Materials and methods: 79 Isolation and stimulation of NK cells: Blood samples from healthy volunteer donors were 80 obtained after approval by the National Healthcare Group Domain Specific Review Board, 81 Singapore (NHG DSRB Ref: 2000/0...

show abstract

Section: Introductionmentioning

confidence: 99%

LAG3 is a Central Regulator of NK Cell Cytokine Production

Narayanan

Ahl

Bijin

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…During virus infection, the host responds by triggering a variety of signaling cascades, especially those involved in the immune response. The activation of these pathways such as the antiviral and pro-inflammatory signaling pathways leads to the induction of an antiviral state that helps the host repress virus replication and clear the virus [27]. In turn, viruses have developed mechanisms to modulate and impair these responses, and often utilize multiple strategies to target these signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

The Potential Role of the ZIKV NS5 Nuclear Spherical-Shell Structures in Cell Type-Specific Host Immune Modulation during ZIKV Infection

Tan

Chan

et al. 2019

Cells

View full text Add to dashboard Cite

The Zika virus (ZIKV) non-structural protein 5 (NS5) plays multiple viral and cellular roles during infection, with its primary role in virus RNA replication taking place in the cytoplasm. However, immunofluorescence assay studies have detected the presence of ZIKV NS5 in unique spherical shell-like structures in the nuclei of infected cells, suggesting potentially important cellular roles of ZIKV NS5 in the nucleus. Hence ZIKV NS5′s subcellular distribution and localization must be tightly regulated during ZIKV infection. Both ZIKV NS5 expression or ZIKV infection antagonizes type I interferon signaling, and induces a pro-inflammatory transcriptional response in a cell type-specific manner, but the mechanisms involved and the role of nuclear ZIKV NS5 in these cellular functions has not been elucidated. Intriguingly, these cells originate from the brain and placenta, which are also organs that exhibit a pro-inflammatory signature and are known sites of pathogenesis during ZIKV infection in animal models and humans. Here, we discuss the regulation of the subcellular localization of the ZIKV NS5 protein, and its putative role in the induction of an inflammatory response and the occurrence of pathology in specific organs during ZIKV infection.

show abstract

“…Various studies have reported that ISGs that are induced upon MAVS activation may establish a positive-feedback loop to potentiate the antiviral signaling at multiple steps (Crosse et al, 2018). For example, the ISG protein DDX60 is an RNA helicase that, upon binding with double-strand RNA, associates with RIG-I, MDA5, and LGP2, and increases MAVS activation (Miyashita et al, 2011).…”

Section: Regulation Of Mavs Signaling By Protein-protein Interactionmentioning

confidence: 99%

Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways

Refolo

Vescovo

Piacentini

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

In the last years, proteomics has represented a valuable approach to elucidate key aspects in the regulation of type I/III interferons (IFNs) and autophagy, two main processes involved in the response to viral infection, to unveil the molecular strategies that viruses have evolved to counteract these processes. Besides their main metabolic roles, mitochondria are well recognized as pivotal organelles in controlling signaling pathways essential to restrain viral infections. In particular, a major role in antiviral defense is played by mitochondrial antiviral signaling (MAVS) protein, an adaptor protein that coordinates the activation of IFN inducing pathways and autophagy at the mitochondrial level. Here, we provide an overview of how mass spectrometry-based studies of protein-protein interactions and post-translational modifications (PTMs) have fostered our understanding of the molecular mechanisms that control the mitochondriamediated antiviral immunity.

show abstract

Interferon-Stimulated Genes as Enhancers of Antiviral Innate Immune Signaling

Cited by 153 publications

References 50 publications

LAG3 is a Central Regulator of NK Cell Cytokine Production

LAG3 is a Central Regulator of NK Cell Cytokine Production

The Potential Role of the ZIKV NS5 Nuclear Spherical-Shell Structures in Cell Type-Specific Host Immune Modulation during ZIKV Infection

Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways

Contact Info

Product

Resources

About