Interferon Lambda Genetics and Biology in Regulation of Viral Control

Hemann, Emily A.; Gale, Michael; Savan, Ram

doi:10.3389/fimmu.2017.01707

Cited by 101 publications

(90 citation statements)

References 144 publications

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“…Subsequently, recruited signal transducer and activator of transcription 1 (STAT1) and STAT2 are activated through phosphorylation leading to the expression of IFN stimulated genes (ISGs), some of which have direct antiviral activities (Dickensheets et al ., 2013). Interferon lambdas are important players in both innate and adaptive immunity and have profound antiviral effects on a variety of viruses (Ank et al ., 2008; Mordstein et al ., 2010; Hemann et al ., 2017; Lee and Baldridge, 2017; Syedbasha and Egli, 2017). Expression of IFNLR1 on epithelial cells of the small intestine and colon was shown to be important in IFN-λ-mediated antiviral activity against persistent MNV and reovirus infection in vivo (Baldridge et al ., 2017).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic suppression of interferon lambda receptor expression leads to enhanced HuNoV replication in vitro

Arthur

Sorgeloos

Hosmillo

et al. 2019

Preprint

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Human norovirus (HuNoV) is the main cause of gastroenteritis worldwide yet no therapeutics are currently available. Here, we utilize a human norovirus replicon in human gastric tumor (HGT) cells to identify host factors involved in promoting or inhibiting HuNoV replication. We observed that an IFN-cured population of replicon-harboring HGT cells (HGT-cured) was enhanced in their ability to replicate transfected HuNoV RNA compared to parental HGT cells, suggesting that differential gene expression in HGT-cured cells created an environment favouring norovirus replication. Microarray analysis was used to identify genes differentially regulated in HGT-NV and HGT-cured compared to parental HGT cells. We found that the IFN lambda receptor alpha (IFNLR1) expression was highly reduced in HGT-NV and HGT-cured cells. All three cell lines responded to exogenous IFN-β by inducing interferon stimulated genes (ISGs), however, HGT-NV and HGT-cured failed to respond to exogenous IFN-λ. Inhibition of DNA methyltransferase activity with 5-aza-2'-deoxycytidine partially reactivated IFNLR1 expression in HGT-NV and IFN-cured cells suggesting that host adaptation occurred via epigenetic reprogramming. In line with this, ectopic expression of the IFN-λ receptor alpha rescued HGT-NV and HGT-cured cells response to IFN-λ. We conclude that type III IFN is important in inhibiting HuNoV replication in vitro and that the loss of IFNLR1 enhances replication of HuNoV. This study unravels for the first time epigenetic reprogramming of the interferon lambda receptor as a new mechanism of cellular adaptation during long-term RNA virus replication and shows that an endogenous level of interferon lambda signalling is able to control human norovirus replication.

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Section: Introductionmentioning

confidence: 99%

Epigenetic suppression of interferon lambda receptor expression leads to enhanced HuNoV replication in vitro

Arthur

Sorgeloos

Hosmillo

et al. 2019

Preprint

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“…Type III IFNs or lambda IFNs use a heterodimeric receptor (IFNLR1-IL10R2) mainly expressed on the epithelial cells. As proof of the key role type III IFNs in the regulation of immunity response, single nucleotide polymorphisms in genes IFNLs were strongly associated with outcomes to viral infection [14]. It has been reported that the homozygosity for IFNL3 (rs12979860) and IFNL4 (rs368234815) variants, overrepresented in African descent, is associated with a reduction of viral clearance in children affected by acute respiratory infections sustained by Rhinovirus and Coronavirus [11].…”

Section: Discussionmentioning

confidence: 99%

PNPLA3 and TLL-1 polymorphisms affect disease severity in patients with COVID-19

Grimaudo¹,

Amodio²,

Pipitone³

et al. 2020

Preprint

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Abstract Introduction Albeit the pathogenesis of COVID-19 remains unclear, host’s genetic polymorphisms in genes infection and reinfection, inflammation, or immune stimulation could play a role in determining the course and outcome. Methods We studied in the early phase of pandemic consecutive patients (N=383) with SARS-CoV-2 infection, whose subsequent clinical course was classified as mild or severe, the latter being characterised by admission to intensive therapy unit or death. Five host gene polymorphisms (MERTK rs4374383, PNPLA3 rs738409, TLL-1 rs17047200, IFNL3 rs1297860, and INFL4 rs368234815) were assessed by using whole nucleic acids extracted from nasopharyngeal swabs. Specific protease cleavage sites of TLL-1 on the SARS-CoV-2 Spyke protein were predicted in silico. Results Male subjects and older patients were significantly at higher risk for a severe outcome (p=0.02 and p<0.001, respectively). By considering patients ≤ 65 years, after adjusting for potential confounding due to sex, an increased risk of severe outcome was found in subjects with the GG genotype of PNPLA3 (adj-OR: 4.69; 95% CI= 1.01-22.04) or TT genotype of TLL-1 (adj-OR=9.1; 95% CI= 1.45-57.3). In silico evaluation showed that TLL-1 is potentially involved in the Spike protein cleavage.Discussion Subjects carrying a GG genotype in PNPLA3 gene might have a constitutive upregulation of the NLRP3 inflammosome and be more prone to tissue damage when infected by SARS-CoV-2. The TT genotype in TLL-1 gene might affect its protease activity on the SARS-CoV-2 Spyke protein, enhancing the ability to infect or re-infect host’s cells. The untoward effect of these variants on disease course is evident in younger patients due to the relative absence of comorbidities as determinants of prognosis.

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“…The airway epithelial cell (AEC) is the point of entry of respiratory viruses and orchestrates the airway immune response in humans 1–5 . Although airway antiviral responses involve many cells, resulting in a complex cytokine milieu, there is agreement that interferon (IFN)‐lambda (type III‐IFN‐λ1) is an antiviral molecule primarily produced by epithelial cells 6–15 . The IFN‐lambda receptor is also predominately expressed in epithelial cells, suggesting that the IFN‐lambda system has evolved to specifically protect mucosal surfaces via paracrine and autocrine mechanisms 6–15 .…”

Section: Introductionmentioning

confidence: 99%

“…Although airway antiviral responses involve many cells, resulting in a complex cytokine milieu, there is agreement that interferon (IFN)‐lambda (type III‐IFN‐λ1) is an antiviral molecule primarily produced by epithelial cells 6–15 . The IFN‐lambda receptor is also predominately expressed in epithelial cells, suggesting that the IFN‐lambda system has evolved to specifically protect mucosal surfaces via paracrine and autocrine mechanisms 6–15 . Notably, there is experimental evidence that IFN lambda provides critical defence against respiratory viruses, including influenza virus and respiratory syncytial virus (RSV) 6–15 .…”

Section: Introductionmentioning

confidence: 99%

“…The IFN‐lambda receptor is also predominately expressed in epithelial cells, suggesting that the IFN‐lambda system has evolved to specifically protect mucosal surfaces via paracrine and autocrine mechanisms 6–15 . Notably, there is experimental evidence that IFN lambda provides critical defence against respiratory viruses, including influenza virus and respiratory syncytial virus (RSV) 6–15 . Emergent data indicate that it may also play an important role against SARS‐CoV‐2 and other type of coronavirus infections 16–21 …”

Section: Introductionmentioning

confidence: 99%

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Innate IFN‐lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life

Salka

Arroyo

Chorvinsky

et al. 2020

Clin Experimental Allergy

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Introduction IFN lambda (type III‐IFN‐λ1) is a molecule primarily produced by epithelial cells that provides an important first‐line defence against viral respiratory infections and has been linked to the pathogenesis of viral‐induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN‐lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. Methods IFN‐lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN‐lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. Results Our in vitro experiments showed that the poly(I:C)‐induced innate production of IFN lambda in human infant AECs is regulated by (a) p38‐MAPK/NF‐kB dependent mechanism; and (b) exposure to pro‐inflammatory signals such as IL1β. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus‐induced IFN‐lambda airway secretion; (b) subjects with RSV infection showed the highest IFN‐lambda airway levels; and (c) individuals with the highest virus‐induced IFN‐lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8). Conclusion IFN‐lambda responses to dsRNA in the human infant airway epithelium are regulated by p38‐MAPK and NF‐kB signalling. High in vivo IFN‐lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children.

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Interferon Lambda Genetics and Biology in Regulation of Viral Control

Cited by 101 publications

References 144 publications

Epigenetic suppression of interferon lambda receptor expression leads to enhanced HuNoV replication in vitro

Epigenetic suppression of interferon lambda receptor expression leads to enhanced HuNoV replication in vitro

PNPLA3 and TLL-1 polymorphisms affect disease severity in patients with COVID-19

Innate IFN‐lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life

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