Suppression of human metapneumovirus (HMPV) infection by the innate sensing gene CEACAM1

Diab, Mohammad; Vitenshtein, Alon; Drori, Yaron; Yamin, Rachel; Danziger, Oded; Zamostiano, Rachel; Mandelboim, Michal; Bacharach, Eran; Mandelboim, Ofer

doi:10.18632/oncotarget.11979

Cited by 9 publications

(10 citation statements)

References 43 publications

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“…Similarly, PERK is activated upon endoplasmic reticulum stress, which might be expected during a viral infection, but not following treatment with IFN alone. Previous reports have shown that carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM1) has antiviral activity against human CMV, influenza virus, and metapneumovirus by suppressing mTOR-mediated protein synthesis (33,34). The membrane protein CEACAM1 is induced by innate sensors such as TLR-4 (35) and IFI16 (34) and delivers inhibitory signals via SHP1 (hematopoietic cells) or SHP2 (epithelial and endothelial cells) phosphatase activity through CEACAM1 ITIMs (36).…”

Section: Discussionmentioning

confidence: 99%

Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells

Holthaus

Vasou

Bamford

et al. 2020

The Journal of Immunology

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IFNs, produced during viral infections, induce the expression of hundreds of IFN-stimulated genes (ISGs). Some ISGs have specific antiviral activity, whereas others regulate the cellular response. Besides functioning as an antiviral effector, ISG15 is a negative regulator of IFN signaling, and inherited ISG15 deficiency leads to autoinflammatory IFNopathies, in which individuals exhibit elevated ISG expression in the absence of pathogenic infection. We have recapitulated these effects in cultured human A549-ISG15 2/2 cells and (using A549-UBA7 2/2 cells) confirmed that posttranslational modification by ISG15 (ISGylation) is not required for regulation of the type I IFN response. ISG15-deficient cells pretreated with IFN-a were resistant to paramyxovirus infection. We also showed that IFN-a treatment of ISG15-deficient cells led to significant inhibition of global protein synthesis, leading us to ask whether resistance was due to the direct antiviral activity of ISGs or whether cells were nonpermissive because of translation defects. We took advantage of the knowledge that IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) is the principal antiviral ISG for parainfluenza virus 5. Knockdown of IFIT1 restored parainfluenza virus 5 infection in IFN-a-pretreated, ISG15-deficient cells, confirming that resistance was due to the direct antiviral activity of the IFN response. However, resistance could be induced if cells were pretreated with IFN-a for longer times, presumably because of inhibition of protein synthesis. These data show that the cause of virus resistance is 2-fold; ISG15 deficiency leads to the early overexpression of specific antiviral ISGs, but the later response is dominated by an unanticipated, ISG15-dependent loss of translational control.

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Section: Discussionmentioning

confidence: 99%

Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells

Holthaus

Vasou

Bamford

et al. 2020

The Journal of Immunology

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“…Similarly, PERK is activated upon endoplasmic reticulum stress which might be expected during a viral infection, but not following treatment with IFN alone. Previous reports have shown that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has antiviral activity against human cytomegalovirus, influenza virus and metapneumovirus by supressing mTOR-mediated protein synthesis (29, 30). The membrane protein CEACAM1 is induced by innate sensors such as TLR-4 (31) and IFI16 (30) and delivers inhibitory signals via SHP1 (haematopoietic cells) or SHP2 (epithelial and endothelial cells) phosphatase activity through CEACAM1 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (32).…”

Section: Discussionmentioning

confidence: 99%

Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells

Holthaus

Vasou

Bamford

et al. 2019

Preprint

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18Interferons (IFNs), produced during viral infections, induce the expression of hundreds of stimulated genes (ISGs). Some ISGs have specific antiviral activity while others regulate the cellular 20 response. In addition to functioning as an antiviral effector, IFN-stimulated gene 15 (ISG15) is a 21 negative regulator of IFN signalling and inherited ISG15-deficiency leads to autoinflammatory 22 interferonopathies where individuals exhibit elevated ISG expression in the absence of infection. We 23 have recapitulated these effects in cultured human A549-ISG15 -/cells and (using A549-UBA7 -/cells) 24 confirmed that posttranslational modification by ISG15 (ISGylation) is not required for regulation of 25 the type-I IFN response. ISG15-deficient cells pre-treated with IFN-α were resistant to paramyxovirus 26 infection. We also showed that IFN-α treatment of ISG15-deficient cells led to significant inhibition 27 of global protein synthesis leading us to ask whether resistance was due to the direct antiviral 28 activity of ISGs or whether cells were non-permissive due to translation defects. We took advantage 29 of the knowledge that IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) is the principal 30 antiviral ISG for parainfluenza virus 5 (PIV5). Knockdown of IFIT1 restored PIV5 infection in IFN-α-31 pre-treated ISG15-deficient cells, confirming that resistance was due to the direct antiviral activity of 32 the IFN response. However, resistance could be induced if cells were pre-treated with IFN-α for 33 longer times, presumably due to inhibition of protein synthesis. These data show that the cause of 34 virus resistance is two-fold; ISG15-deficiency leads to the 'early' over-expression of specific antiviral 35ISGs, but the later response is dominated by an unanticipated, ISG15-dependent, loss of 36 translational control. 37 FBS (1:1000). Following PBS washes, cells were incubated for 1 h with goat anti-mouse IgG 131 antibodies conjugated to alkaline phosphatase (Abcam Cat# ab97020) diluted 1:1000 in PBS, 3%FBS. 132 Cells were washed in PBS and signals were detected using SIGMAFAST BCIP/NBT (Sigma). 133 Reverse transcription quantitative PCR. 134Total cellular RNA was purified from cells that had been treated with 1000 IU/ml IFN-α2b (Intron A) 135 for 18 h, or left untreated, using TRIzol reagent (ThermoFisher Scientific) and Direct-zol RNA 136

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“…NK cells are known mostly for their role in controlling viral infections (20,21) and have been shown to be involved in cytomegalovirus (CMV) (22)(23)(24), influenza virus (6,(25)(26)(27)(28), Newcastle disease virus (29), vaccinia virus (30), and human metapneumovirus (HMPV) infections (31,32). NK cells express a large repertoire of inhibitory receptors, which mostly recognize major histocompatibility complex class I (MHC-I) molecules (missing self hypothesis [33]).…”

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confidence: 99%

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

Glasner

Oiknine‐Djian

Weisblum

et al. 2017

J Virol

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NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-␤). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus.IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus infection is largely unknown. Here we demonstrate that Zika virus infection is almost undetected by NK cells, as evidenced by the fact that the expression of activating ligands for NK cells is not induced following Zika infection. We identified a mechanism whereby Zika virus sensing via the RIGI-IRF3 pathway resulted in IFN-␤-mediated upregulation of MHC-I molecules and inhibition of NK cell activity. Countering MHC class I upregulation and boosting NK cell activity may be employed as prophylactic measures to combat Zika virus infection.KEYWORDS Zika virus, MHC class I, NK cells, NK escape mechanisms N K cells are lymphocytes belonging to the innate immune system. NK cells participate in many immunological activities, from killing cancerous cells (1-7) and fighting bacteria (8-10) and fungi (11) to playing roles in allergy (12) and graft-versushost disease (13). NK cells also play roles in autoimmunity (14-18) and pregnancy (19).

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Suppression of human metapneumovirus (HMPV) infection by the innate sensing gene CEACAM1

Cited by 9 publications

References 43 publications

Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells

Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells

Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

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