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Introduction: This study aimed to investigate if gene expression modifications due to two different single nucleotide polymorphism (SNP) mutations within the interferon-α/β receptor-2 (IFNAR2) gene had an effect on clinical prognosis in pregnant coronavirus disease 2019 (COVID-19) patients.Methodology: The study included 173 pregnant patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using real-time polymerase chain reaction (RT-PCR). Oligonucleotides were designed for the SNPs with nucleotide database codes rs13050728 and rs2236757 in the hospital’s genetic laboratory, and RT-PCR analyses were performed.Results: There was a significant difference in upper respiratory tract infection (URTI) symptoms (runny nose, nasal congestion, and fatigue); between rs2236757 normal–carrier–homozygous mutant pregnant women and the occurrence of symptoms (p = 0.004). However, these URTI symptoms were never seen in homozygous mutant pregnant women. Upon analysis of the relationship between rs13050728 normal–carrier–homozygous mutant pregnant women and the occurrence of symptoms, there was a significant difference between URTI symptoms, and nausea and vomiting (p = 0.001, p = 0.027, respectively). The URTI symptoms were never seen in homozygous mutant and carrier pregnant women. There was no significant association between rs13050728 and rs2236757 normal–carrier–homozygous mutant pregnant women and severity of disease, intensive care unit admission, pregnancy complications, need for oxygen support, and radiologic involvement.Conclusions: The results of this study will serve as a guide in identifying high-risk individuals, providing treatment, and contributing to the understanding of genetic factors in future viral pandemics.

Interferons (IFNs) are a group of cytokines with antiviral, antiproliferative, antiangiogenic, and immunomodulatory activities. Type I IFNs amplify and propagate the antiviral response by interacting with their receptors, IFNAR1 and IFNAR2. In COVID-19, the IFNAR2 (interferon alpha and beta receptor subunit 2) gene has been associated with the severity of the disease, but the soluble receptor (sIFNAR2) levels have not been investigated. We aimed to evaluate the association of IFNAR2 variants (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) with COVID-19 mortality and to assess if there was a relation between the genetic variants and/or the clinical outcome, with the levels of sIFNAR2 in plasma samples from hospitalized individuals with severe COVID-19. We included 1,202 subjects with severe COVID-19. The genetic variants were determined by employing Taqman ® assays. The levels of sIFNAR2 were determined with ELISA in plasma samples from a subgroup of 351 individuals. The rs2236757, rs3153, rs1051393, and rs2834158 variants were associated with mortality risk among patients with severe COVID-19. Higher levels of sIFNAR2 were observed in survivors of COVID-19 compared to the group of non-survivors, which was not related to the studied IFNAR2 genetic variants. IFNAR2, both gene, and soluble protein, are relevant in the clinical outcome of patients hospitalized with severe COVID-19.

Influenza virus infections particularly when followed by bacterial superinfections (BSI) result in significant morbidities and mortalities especially during influenza pandemics. Type I interferons (IFNs) regulate both anti-influenza immunity and host susceptibility to subsequent BSIs. These type I IFNs consisting of, among others, 14 IFN-α's and a single IFN-β, are recognized by and signal through the heterodimeric type I IFN receptor (IFNAR) comprised of IFNAR1 and IFNAR2. However, the individual receptor subunits can bind IFN-β or IFN-α's independently of each other and induce distinct signaling. The role of type I IFN signaling in regulating host susceptibility to both viral infections and BSI has been only examined with respect to IFNAR1 deficiency. Here, we demonstrate that despite some redundancies, IFNAR1 and IFNAR2 have distinct roles in regulating both anti-influenza A virus (IAV) immunity and in shaping host susceptibility to subsequent BSI caused by . We found IFNAR2 to be critical for anti-viral immunity. In contrast to mice, IAV-infected mice displayed both increased and accelerated morbidity and mortality compared to WT mice. Furthermore, unlike IFNAR1, IFNAR2 was sufficient to generate protection from lethal IAV infection when stimulated with IFN-β. With regards to BSI, unlike what we found previously in mice, mice were not susceptible to BSI induced on day 3 post-IAV, even though absence of IFNAR2 resulted in increased viral burden and an increased inflammatory environment. The mice similar to what we previously found in mice were less susceptible than WT mice to BSI induced on day 7 post-IAV, indicating that signaling through a complete receptor increases BSI susceptibility late during clinical IAV infection. Thus, our results support a role for IFNAR2 in induction of anti-IAV immune responses that are involved in altering host susceptibility to BSI and are essential for decreasing the morbidity and mortality associated with IAV infection. These results begin to elucidate some of the mechanisms involved in how the individual IFNAR subunits shape the anti-viral immune response. Moreover, our results highlight the importance of examining the contributions of entire receptors, as individual subunits can induce distinct outcomes as shown here.

Receiving the measles vaccination is crucial for controlling the disease and preventing severe complications. However, adverse reactions can occur in individuals with inborn errors of immunity. This case report details a severe reaction to the measles vaccine in a ten-month-old female with a homozygous mutation in the IFNAR2 gene, leading to immunodeficiency-45. Following vaccination, she developed viremia, meningoencephalitis, and multi-organ failure. Genetic analysis identified a Variant of Uncertain Significance (VUS) in the IFNAR2 gene, which is essential for type I interferon (IFN-I) signaling. This case highlights the importance of incorporating genetic screening into vaccination programs for individuals at risk. It demonstrates the complex relationship between genetic mutations and the immune responses to the vaccines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a wide range of clinical manifestations modulated by genetic factors. The aim of this study was to identify genetic determinants of severe COVID-19 affecting protein sequence to gain insight into disease pathogenesis. Variants prioritized in two patients requiring lung transplant were tested in the Milan FOGS cohort (487/869 cases/controls), highlighting an independent association between the p.F8S low-frequency variant of interferon alpha receptor 2 gene (IFNAR2) and severe disease (OR = 1.73 [1.24–2.42], p = 0.001), replicated in the COVID-19 Host Genetics Initiative cohort (26,167/2,061,934 cases/controls). In the FOGS cohort, the p.F8S variant was linked to higher circulating IL-6 levels. In keeping, bulk transcriptomic analysis in PBMCs at the peak of infection (n = 57) showed that carriers of the p.F8S variant had upregulation of immune signaling and pathogens response (p < 0.05). Functional flow cytometry experiments in healthy donors (n = 12) revealed that membrane IFNAR2 protein expression was reduced in B lymphocytes, but higher in dendritic cells (p < 0.05). Finally, by interrogating a public scRNAseq resource of PBMC of people with COVID-19, we showed that p.F8S carriers had upregulation of immune pathways specifically in dendritic cells (p < 0.05). These results suggest that the p.F8S variant may influence COVID-19 severity by enhancing adaptive immune response, thereby favoring inflammation.

Although advanced age, male sex, and some comorbidities impact the clinical course of COVID-19, these factors only partially explain the inter-individual variability in disease severity. Some studies have shown that genetic polymorphisms contribute to COVID-19 severity; however, the results are inconclusive. Thus, we investigated the association between polymorphisms in ACE1, ACE2, DPP9, IFIH1, IFNAR2, IFNL4, TLR3, TMPRSS2, and TYK2 and the clinical course of COVID-19. A total of 694 patients with COVID-19 were categorized as: (1) ward inpatients (moderate symptoms) or patients admitted at the intensive care unit (ICU; severe symptoms); and (2) survivors or non-survivors. In females, the rs1990760/IFIH1 T/T genotype was associated with risk of ICU admission and death. Moreover, the rs1799752/ACE1 Ins and rs12329760/TMPRSS2 T alleles were associated with risk of ICU admission. In non-white patients, the rs2236757/IFNAR2 A/A genotype was associated with risk of ICU admission, while the rs1799752/ACE1 Ins/Ins genotype, rs2236757/IFNAR2 A/A genotype, and rs12329760/TMPRSS2 T allele were associated with risk of death. Moreover, some of the analyzed polymorphisms interact in the risk of worse COVID-19 outcomes. In conclusion, this study shows an association of rs1799752/ACE1, rs1990760/IFIH1, rs2236757/IFNAR2, rs12329760/TMPRSS2, and rs2304256/TYK2 polymorphisms with worse COVID-19 outcomes, especially among female and non-white patients.

Mitophagy receptor-related genes (MRRGs) orchestrate mitochondrial quality control and may shape glioma progression and immune tolerance, yet their integrated prognostic and immunobiological significance remains unclear. We combined WGCNA, single-cell AUCell scoring, and LASSO/Cox modeling across public glioma cohorts to derive and externally validate a 17-gene MRRG risk signature. Multi-omics comparisons (transcriptome, pathway enrichment, mutation, and GWAS association), immune infiltration, and therapy response prediction were performed. Core driver(s) were interrogated by functional assays and xenograft validation. The MRRG signature robustly stratified overall survival across independent datasets and remained an independent prognostic factor after multivariable adjustment. High-risk tumors exhibited activation of P53 signaling and MAPK signaling pathway, coupled with immunosuppressive remodeling characterized by increased M2-like macrophage infiltration and T cell dysfunction. Integrative analyses highlighted IFNAR2 as a central node; its silencing impaired glioma cell proliferation, invasion, and metastatic potential, while suppression attenuated tumor growth. The model correlated with differential predicted sensitivity to immunotherapy and targeted agents, suggesting potential for precision stratification. We present and validate a 17-MRRG prognostic model that links mitophagy receptors to glioma immunosuppression and clinical outcome, and identify IFNAR2 as a functional driver. These findings provide a rationale for incorporating MRRG profiling into prognostic assessment and therapeutic decision-making in glioma.

African swine fever (ASF) is a highly contagious and severe hemorrhagic disease caused by African swine fever virus (ASFV). Currently, few safe and effective vaccines or antiviral drugs are available for its prevention. Interferon (IFN), a key component of innate antiviral immunity, induces interferon-stimulated genes (ISGs) by activating the JAK-STAT signalling pathway, resulting in antiviral effects. ASFV strains, including ASFV SY18, ASFV HLJ18, and ASFV BA71V, are highly sensitive to IFN-I treatment; however, the mechanisms by which ASFV antagonizes the host type I IFN response have not been fully elucidated. In this study, we identified the ASFV B125R protein (pB125R) as a negative regulator of the JAK-STAT pathway. We observed that ectopically expressed pB125R significantly suppressed the IFN-β-triggered activation of JAK-STAT signalling in HEK293T and PK-15 cells. Mechanistic studies revealed that pB125R binds to IFNAR2 and promotes its autophagic degradation, impairing the signal transduction of the IFN response at an early stage. This ultimately reduces the nuclear translocation of the ISGF3 complex and decreases ISG production. Our findings highlight the immunosuppressive activity of pB125R and reveal a novel mechanism by which ASFV evades the host IFN response, contributing to potential strategies for developing vaccines and therapeutics against ASF.

Type I interferon (IFN-I) exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections. In this study, we unveil SENP6 as a potent regulator of IFN-I antiviral activity. SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling. Mechanistically, SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8, consequently restricting the interaction between USP8 and IFNAR2. The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation, thus attenuating IFN-I antiviral activity. Correspondingly, the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2, leading to a reduction in IFNAR2 ubiquitination and, consequently, an enhancement in IFN-I-induced signaling. This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.