Antiviral, Immunomodulatory and Antiproliferative Activities of Recombinant Soluble IFNAR2 without IFN-ß Mediation

Hernáez, Bruno; Pinto-Medel, María Jesús; Calonge, Esther; Rodriguez-Bada, J.L.; Hurtado-Guerrero, Isaac; Alonso, Ana; Mena-Vázquez, Natalia; Aliaga, Pablo; Issazadeh‐Navikas, Shohreh; Pavía, J.; Leyva, Laura; Alcamı́, José; Alcamı́, Antonio; Fernández, Óscar; Oliver-Martos, Begoña

doi:10.3390/jcm9040959

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…Notably, IFNAR2 is capable of producing soluble receptors, which binds and regulates endogenous production of type I IFNs ( 17 , 18 ). This soluble IFNAR2 possesses both anti-proliferative and antiviral functions as well as therapeutic properties ( 19 ). In particular, in COVID-19, a protective role of IFNAR2 has been suggested ( 6 , 20 ).…”

Section: Discussionmentioning

confidence: 99%

Unraveling Risk Genes of COVID-19 by Multi-Omics Integrative Analyses

2021

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Objectives: Uncovering the genetic basis of COVID-19 may shed insight into its pathogenesis and help to improve treatment measures. We aimed to investigate the host genetic variants associated with COVID-19.Methods: The summary result of a COVID-19 GWAS (9,373 hospitalized COVID-19 cases and 1,197,256 controls) was obtained from the COVID-19 Host Genetic Initiative GWAS meta-analyses. We tested colocalization of the GWAS signals of COVID-19 with expression and methylation quantitative traits loci (eQTL and mQTL, respectively) using the summary data-based Mendelian randomization (SMR) analysis. Four eQTL and two mQTL datasets were utilized in the SMR analysis, including CAGE blood eQTL data (n = 2,765), GTEx v7 blood (n = 338) and lung (n = 278) eQTL data, Geuvadis lymphoblastoid cells eQTL data, LBC-BSGS blood mQTL data (n = 1,980), and Hannon blood mQTL summary data (n = 1,175). We conducted a transcriptome-wide association study (TWAS) on COVID-19 with precomputed prediction models of GTEx v8 eQTL in lung and blood using S-PrediXcan.Results: Our SMR analyses identified seven protein-coding genes (TYK2, IFNAR2, OAS1, OAS3, XCR1, CCR5, and MAPT) associated with COVID-19, including two novel risk genes, CCR5 and tau-encoding MAPT. The TWAS revealed four genes for COVID-19 (CXCR6, CCR5, CCR9, and PIGN), including two novel risk genes, CCR5 and PIGN.Conclusion: Our study highlighted the functional relevance of some known genome-wide risk genes of COVID-19 and revealed novel genes contributing to differential outcomes of COVID-19 disease.

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Section: Discussionmentioning

confidence: 99%

Unraveling Risk Genes of COVID-19 by Multi-Omics Integrative Analyses

2021

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“…However, its role in the immune system is mostly unknown, despite that the human form was first cloned in 1995 ( 15 ). Therefore, we cloned a recombinant form analogous to human soluble IFNAR2 and recently demonstrated that it exerts antiviral, immunomodulatory and antiproliferative activities without IFN-β mediation ( 35 ). Regarding the native form, we developed an ELISA to detect sIFNAR2 in serum that was analytically validated ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Soluble Receptor Isoform of IFN-Beta (sIFNAR2) in Multiple Sclerosis Patients and Their Association With the Clinical Response to IFN-Beta Treatment

et al. 2021

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PurposeInterferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the in vitro short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients.MethodsNinety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation in vitro.ResultsProtein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β in vitro induction of PBMC, 6/7 patients increased the sIFNAR2 expression.ConclusionsIFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.

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“…The COVID-19 Host Genetics Initiative (HGI) is constantly updating its GWAS meta-analysis (latest HGI version 6 available at https://www.covid19hg.org/results/r6/) 21 . GWAS have identified various loci associated with susceptibility to infection or severity of COVID-19 22 , which were later confirmed by colocalization analysis 23 or Mendelian Randomization (MR) 24 . The most consistent region identified among several GWAS associated with severe COVID-19 is at 3p21.31 chromosomal region, which includes several genes, including SLC6A20 25 .…”

Section: Introductionmentioning

confidence: 95%

ACE2, TMPRSS2, TYK2, SLC6A20, and IFNAR2 human genes variants influence SARS‑CoV‑2 infection susceptibility

Aghamirli,

Saleh-Gohari

2023

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The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) causes a global pandemic named COVID-19. That virus causes a range of human respiratory tract infections; that severity varies from relatively mild to severe respiratory injury syndrome. It has indicated that some individuals might offer susceptibility to SARS‐CoV‐2 infection due to genetic factors. ACE2, TMPRSS2, TYK2, SLC6A20, and IFNAR2 human genes are involved in the pathogenesis of coronavirus in various populations and geographic territories; Therefore, examining the genetic variants of these genes can determine their association with the severity of the COVID-19 disease. In this study, the Whole-Exome Sequencing (WES) technique was used to identify variants of the mentioned human genes concerning the presence or absence of SARS‐CoV‐2 infection in the cohort of 100 individuals from Iran; that may modulate viral infectivity and make some individuals more vulnerable than others. Next, the frequency of variants found in the Iranian population was compared with those belonging to reference individuals from the 1000 Genomes Project, genomAD, and ExAC. In addition, due to the extraordinary importance of the protein’s three-dimensional structure in maintaining the optimal function of the protein, also protein modeling was performed for the essential found variants. The ACE2 gene showed a high level of polymorphism. While TMPRSS2 is less polymorphic. The variants rs759499720/ACE2، rs776459296/ACE2، rs386818798/TMPRSS2، rs771922681/TYK2، rs753470142/TYK2، c.675G>T/TYK2، rs147760034/SLC6A20، rs139008024/SLC6A20, and rs759744926/IFNAR2 showed a significant association with SARS-CoV-2 infection and COVID-19. These variants have previously been detected in studies.

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Antiviral, Immunomodulatory and Antiproliferative Activities of Recombinant Soluble IFNAR2 without IFN-ß Mediation

Cited by 7 publications

References 48 publications

Unraveling Risk Genes of COVID-19 by Multi-Omics Integrative Analyses

Unraveling Risk Genes of COVID-19 by Multi-Omics Integrative Analyses

Soluble Receptor Isoform of IFN-Beta (sIFNAR2) in Multiple Sclerosis Patients and Their Association With the Clinical Response to IFN-Beta Treatment

ACE2, TMPRSS2, TYK2, SLC6A20, and IFNAR2 human genes variants influence SARS‑CoV‑2 infection susceptibility

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