Shared and Distinct Functions of Type I and Type III Interferons

Lazear, Helen M.; Schoggins, John W.; Diamond, Michael S.

doi:10.1016/j.immuni.2019.03.025

Cited by 863 publications

(930 citation statements)

References 227 publications

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“…In this review, we will focus on type-I IFNs. An overview of the three types of IFNs has been extensively reviewed elsewhere (Borden et al, 2007;González-Navajas et al, 2012;Kim et al, 2016;Lazear et al, 2019;Mesev et al, 2019;Wack et al, 2015).…”

Section: Ifn Families and Type-i Ifnsmentioning

confidence: 99%

Type-I interferons in atherosclerosis

Chen

Tas

Winther

2019

Journal of Experimental Medicine

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The contribution of dyslipidemia and inflammation in atherosclerosis is well established. Along with effective lipid-lowering treatments, the recent success of clinical trials with anti-inflammatory therapies and the accelerated atherosclerosis in many autoimmune diseases suggest that targeting inflammation may open new avenues for the prevention and the treatment for cardiovascular diseases (CVDs). In the past decades, studies have widened the role of type-I interferons (IFNs) in disease, from antivirus defense to autoimmune responses and immuno-metabolic syndromes. While elevated type-I IFN level in serum is associated with CVD incidence in patients with interferonopathies, experimental data have attested that type-I IFNs affect plaque-residing macrophages, potentiate foam cell and extracellular trap formation, induce endothelial dysfunction, alter the phenotypes of dendritic cells and T and B lymphocytes, and lead to exacerbated atherosclerosis outcomes. In this review, we discuss the production and the effects of type-I IFNs in different atherosclerosis-associated cell types from molecular biology studies, animal models, and clinical observations, and the potential of new therapies against type-I IFN signaling for atherosclerosis.

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Section: Ifn Families and Type-i Ifnsmentioning

confidence: 99%

Type-I interferons in atherosclerosis

Chen

Tas

Winther

2019

Journal of Experimental Medicine

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“…Interferons (IFN) are cytokines that establish an antiviral cellular state through transcriptional induction of interferon-stimulated genes (ISGs) (1). Following engagement of IFN (type I and type III) with its cognate cell surface receptors, a JAK-STAT signaling cascade is activated that results in the formation of the ISGF3 transcription factor complex that binds to IFN response elements in the promoters of ISGs.…”

Section: Introductionmentioning

confidence: 99%

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Williams

Gokhale

Snider

et al. 2020

Preprint

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AbstractType I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection is unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2’O methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2’O methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.ImportanceInduction of an efficient type I IFN response is important to control viral infection. We show that the host 2’O methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of these mRNAs lacking cap 2’O methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.

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“…After initial sensing, activation of subsequent signalling cascades leads to nuclear translocation of the transcription factors interferon regulatory factor (IRF) 3, IRF7 and NF-κB, which drives expression of antiviral molecules such as interferons (IFNs) and other pro-inflammatory cytokines. Type I IFNs (IFN-α/β) and type III IFNs (IFN-λ) induce expression of interferon-stimulated genes (ISGs) with the distinction that, due to receptor restrictions, IFN-λ can only induce ISGs in epithelial cells, whereas ISGs induced by type I IFNs can be expressed by virtually any cell type (14, 15). ISGs are antiviral effector proteins that limit virus replication and spread.…”

Section: Introductionmentioning

confidence: 99%

The deubiquitinating activity of Middle East respiratory syndrome coronavirus papain-like protease delays the innate immune response and enhances virulence in a mouse model

Knaap

Fernández‐Delgado

Dalebout

et al. 2019

Preprint

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16Middle East respiratory syndrome coronavirus (MERS-CoV) continues to cause zoonotic infections 17 and serious disease, primarily in the Arabian Peninsula, due to repeated spill-over from dromedary 18 camels and subsequent nosocomial transmission. Approved MERS vaccines for use in animals or 19 humans are not currently available. MERS-CoV replication requires the virus-encoded papain-like 20 protease (PL pro ) to cleave multiple sites in the viral replicase polyproteins, thereby releasing 21 functional non-structural proteins. Additionally, PL pro is a deubiquitinating enzyme (DUB) that can 22 remove ubiquitin(-like) moieties from substrates, presumably to counteract host antiviral responses. 23 In previous work, we determined the crystal structure of MERS-CoV PL pro in complex with ubiquitin, 24 facilitating the design of PL pro mutations that impair DUB activity without affecting viral polyprotein 25 cleavage. Here, we introduced these DUB-inactivating mutations into the viral genome and 26 examined their impact on MERS-CoV infection both in cell culture and in a lethal mouse model. 27 Although overall replication of DUB-negative and wild-type (wt) recombinant MERS-CoV was 28 comparable in multiple cell lines, infection with DUB-negative virus markedly increased mRNA levels 29 for interferon (IFN)-β and IFN-stimulated genes. Moreover, compared to a wt virus infection, the 30 survival rate was significantly increased when DUB-negative MERS-CoV was used to infect transgenic 31 mice expressing a human MERS-CoV receptor. Interestingly, DUB-negative and wt MERS-CoV 32 replicated to the same titers in lungs of infected mice, but the DUB-negative virus was cleared faster, 33 likely due to the observed accelerated and better-regulated innate immune responses, in contrast to 34 delayed and subsequently excessive responses in wt virus-infected mice. This study provides the first 35 direct evidence that the DUB activity of a coronaviral protease contributes to innate immune evasion 36 and can profoundly enhance virulence in an animal model. Thus, reduction or removal of the innate 37 immune-suppressive DUB activity of PL pro s is a promising strategy for coronavirus attenuation in the 38 context of rational vaccine development.

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Shared and Distinct Functions of Type I and Type III Interferons

Cited by 863 publications

References 227 publications

Type-I interferons in atherosclerosis

Type-I interferons in atherosclerosis

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

The deubiquitinating activity of Middle East respiratory syndrome coronavirus papain-like protease delays the innate immune response and enhances virulence in a mouse model

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