The interferon stimulated gene viperin, restricts Shigella. flexneri in vitro

Helbig, Karla J.; Teh, Min Yan; Monson, Ebony A; Smith, Monique; Tran, Elizabeth Ngoc Hoa; Standish, Alistair J.; Morona, Renato; Beard, Michael R.

doi:10.1038/s41598-019-52130-8

Cited by 17 publications

(15 citation statements)

References 62 publications

(85 reference statements)

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“…Lastly, viperin has been shown to be induced by microbial constituents and inhibit the infection of some bacteria such as Shigella flexneri and Listeria monocytogenes (93). For S. flexneri, the current model is linked to viperin-induced changes in cellular cholesterol levels that impair bacterial entry (93). Similar effects on cholesterol levels have been linked to viperin's antiviral activity against several viruses, including IAV, HIV, and rabies virus (70,86).…”

Section: Discussionmentioning

confidence: 97%

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Viperin Reveals Its True Function

et al. 2020

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Most cells respond to viral infections by activating innate immune pathways that lead to the induction of antiviral restriction factors. One such factor, viperin, was discovered almost two decades ago based on its induction during viral infection. Since then, viperin has been shown to possess activity against numerous viruses via multiple proposed mechanisms. Most recently, however, viperin was demonstrated to catalyze the conversion of cytidine triphosphate (CTP) to 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP), a previously unknown ribonucleotide. Incorporation of ddhCTP causes premature termination of RNA synthesis by the RNA-dependent RNA polymerase of some viruses. To date, production of ddhCTP by viperin represents the only activity of viperin that links its enzymatic activity directly to an antiviral mechanism in human cells. This review examines the multiple antiviral mechanisms and biological functions attributed to viperin. Expected final online publication date for the Annual Review of Virology, Volume 7 is September 29, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Viperin Reveals Its True Function

et al. 2020

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“…Members of the interferon (IFN)-induced transmembrane (IFITM) protein family have been shown to restrict intracellular growth of Mycobacterium tuberculosis (MTb) probably through their mediation in endosomal maturation [ 18 ]. The ISG viperin has been shown to inhibit the growth of Shigella flexneri , an intracellular bacteria, in vitro [ 19 ]. A cell-based screen with over 350 human genes identified six ISGs, including PKRD2 , UNC93B1 , MYD88 , AQP9 , MAP3K14 , and TRIM14 , that robustly inhibited Listeria monocytogenes infection [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis

et al. 2021

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Toll-like receptors (TLRs) are highly-conserved pattern recognition receptors that mediate innate immune responses to invading pathogens and endogenous danger signals released from damaged and dying cells. Activation of TLRs trigger downstream signaling cascades, that culminate in the activation of interferon regulatory factors (IRFs), which subsequently leads to type I interferon (IFN) response. In the current study, we sought to expand the scope of gene expression changes in THP1-derived macrophages upon TLR4 activation and to identify interferon-stimulated genes. RNA-seq analysis led to the identification of several known and novel differentially expressed genes, including CMPK2, particularly in association with type I IFN signaling. We performed an in-depth characterization of CMPK2 expression, a nucleoside monophosphate kinase that supplies intracellular UTP/CTP for nucleic acid synthesis in response to type I IFN signaling in macrophages. CMPK2 was significantly induced at both RNA and protein levels upon stimulation with TLR4 ligand—LPS and TLR3 ligand—Poly (I:C). Confocal microscopy and subcellular fractionation indicated CMPK2 localization in both cytoplasm and mitochondria of THP-1 macrophages. Furthermore, neutralizing antibody-based inhibition of IFNAR receptor in THP-1 cells and BMDMs derived from IFNAR KO and IRF3 KO knockout mice further revealed that CMPK2 expression is dependent on LPS/Poly (I:C) mediated IRF3- type I interferon signaling. In summary, our findings suggest that CMPK2 is a potential interferon-stimulated gene in THP-1 macrophages and that CMPK2 may facilitate IRF3- type I IFN-dependent anti-bacterial and anti-viral roles.

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“…Although the functions of IFNλ and ISGs have been predominantly studied in the context of viral infection ( 62 , 63 ), emerging evidence indicates a protective role of some ISGs in bacterial infection. For example, the anti-viral IF N i nduced t rans m embrane (IFITM) proteins have been shown to restrict Mycobacterium tuberculosis intracellular growth ( 64 ) and the ISG Viperin inhibits the entry of Shigella into epithelial cells ( 65 ). Additionally, g uanylate- b inding p roteins (GBPs) bind the LPS of Gram-negative bacteria, facilitating activation of the non-canonical inflammasome ( 66 – 69 ).…”

Section: Type III Interferon Induction and Signalingmentioning

confidence: 99%

Functions of IFNλs in Anti-Bacterial Immunity at Mucosal Barriers

et al. 2022

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Type III interferons (IFNs), or IFNλs, are cytokines produced in response to microbial ligands. They signal through the IFNλ receptor complex (IFNLR), which is located on epithelial cells and select immune cells at barrier sites. As well as being induced during bacterial or viral infection, type III IFNs are produced in response to the microbiota in the lung and intestinal epithelium where they cultivate a resting antiviral state. While the multiple anti-viral activities of IFNλs have been extensively studied, their roles in immunity against bacteria are only recently emerging. Type III IFNs increase epithelial barrier integrity and protect from infection in the intestine but were shown to increase susceptibility to bacterial superinfections in the respiratory tract. Therefore, the effects of IFNλ can be beneficial or detrimental to the host during bacterial infections, depending on timing and biological contexts. This duality will affect the potential benefits of IFNλs as therapeutic agents. In this review, we summarize the current knowledge on IFNλ induction and signaling, as well as their roles at different barrier sites in the context of anti-bacterial immunity.

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The interferon stimulated gene viperin, restricts Shigella. flexneri in vitro

Cited by 17 publications

References 62 publications

Viperin Reveals Its True Function

Viperin Reveals Its True Function

UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis

Functions of IFNλs in Anti-Bacterial Immunity at Mucosal Barriers

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