Constitutive IFNα/β signaling maintains expression of signaling intermediaries for efficient cytokine responses

Messina, Nicole L.; Clarke, Christopher J.; Johnstone, Ricky W.

doi:10.1080/21623996.2016.1173804

Cited by 3 publications

(3 citation statements)

References 61 publications

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“…In this study, we have identified miR-203a-3p, which is induced upon RNA virus infection and poly(I:C) transfection. miR-203a-3p targets the 3'UTR of the IFNA pathway genes (IFNAR1, IFNA2, 4,7,10,14,16,17,21). We confirmed that miR-203a-3p forms a complex with Argonaut 2 (Ago2) protein, subsequently recruiting it to the transcripts of IFNA signaling pathway genes, including JAK1 and STAT1.…”

Section: Introductionsupporting

confidence: 52%

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MicroRNA hsa-miR-203a-3p promotes H1N1 and NDV Virus Replication by suppressing the IFNA signaling

kumar,

Kumar,

Kumar

et al. 2024

Preprint

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MicroRNAs (miRNAs) are small non-coding molecules that act as essential post-transcriptional regulators in various biological processes. Many studies suggest that miRNAs may modulate the host's immune response during virus infections. We analyzed publicly available transcriptomics data involving infection with different RNA viruses and selected the most prominent candidate, miR-203a-3p. miR-203a-3p is upregulated during H7N1, HCV, and HIV+HPV infections. Interestingly, pathway analysis of microRNA-targeted genes shows that miR-203a-3p targets the type–I interferon pathway. In this study, we report that the expression of miR-203a-3p is elevated in response to polyinosinic-polycytidylic acid [poly(I:C)] transfection and infection with RNA viruses like Newcastle Disease Virus (NDV) and H1N1 influenza virus. We found that overexpression of miR-203-3p promotes the replication of H1N1 virus by suppressing the host's type-I interferons and interferon-stimulated genes. In addition, miR-203a-3p overexpression reduced the expression of ISGs, and is attributed to the binding of miR-203a-3p to 3' UTRs of Janus-activated kinase 1 (JAK1), STAT1, SOCS3, and multiple IFNA transcripts, as shown by luciferase and Ago-2 pulldown assays. Altogether, these findings strongly suggest that miR-203a-3p acts as a pro-viral molecule during H1N1 and NDV infection by targeting the host's IFN signaling pathways.

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Section: Introductionsupporting

confidence: 52%

“…The type-I interferons (specially IFNα/β) are well characterized for the primary innate immune response and are necessary for defending against viruses (16)(17)(18). Type-I interferons are a family of cytokines dedicated to immunity against viruses, bacteria, parasites, and fungi.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA hsa-miR-203a-3p promotes H1N1 and NDV Virus Replication by suppressing the IFNA signaling

kumar,

Kumar,

Kumar

et al. 2024

Preprint

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“…All type I interferons signal through a common receptor interferon alpha receptor (IFNAR). The IFNAR induces the Janus activated kinase-signal transducer and activation of transcription (JAK-STAT) pathway that control a large collection of genes through regulated expression of various signaling intermediaries (Guan et al, 2014;Messina et al, 2016;Olex et al, 2016).…”

Section: Role Of Human Interferons In Viral and Non-viral Liver Diseasementioning

confidence: 99%

A Role of Variance in Interferon Genes to Disease Severity in COVID-19 Patients

et al. 2021

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The rapid rise and global consequences of the novel coronavirus disease 19 (COVID-19) have again brought the focus of the scientific community on the possible host factors involved in patient response and outcome to exposure to the virus. The disease severity remains highly unpredictable, and individuals with none of the aforementioned risk factors may still develop severe COVID-19. It was shown that genotype-related factors like an ABO Blood Group affect COVID-19 severity, and the risk of infection with SARS-CoV-2 was higher for patients with blood type A and lower for patients with blood type O. Currently it is not clear which specific genes are associated with COVID-19 severity. The comparative analysis of COVID-19 and other viral infections allows us to predict that the variants within the interferon pathway genes may serve as markers of the magnitude of immune response to specific pathogens. In particular, various members of Class III interferons (lambda) are reviewed in detail.

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Neuronal Ablation of Alpha/Beta Interferon (IFN-α/β) Signaling Exacerbates Central Nervous System Viral Dissemination and Impairs IFN-γ Responsiveness in Microglia/Macrophages

Hwang

Bergmann

2020

J Virol

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IFNα/β signaling through the IFNα/β receptor (IFNAR) is essential to limit virus dissemination throughout the central nervous system (CNS) following many neurotropic virus infections. However, the distinct expression pattern of factors associated with the IFNα/β pathway in different CNS resident cell populations implicate complex cooperative pathways in IFNα/β induction and responsiveness. Herein we show that mice devoid of IFNAR1 signaling in calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) expressing neurons (CaMKIIcre:IFNARfl/fl mice) infected with a mildly pathogenic neurotropic coronavirus (MHV-A59) developed severe encephalomyelitis with hind-limb paralysis and succumbed within 7 days. Increased virus spread in CaMKIIcre:IFNARfl/fl mice compared to IFNARfl/fl mice not only affected neurons in the forebrain, but also the mid-hind brain and spinal cords, but excluded the cerebellum. Infection was also increased in glia. The lack of viral control in CaMKIIcre:IFNARfl/fl relative to control mice coincided with sustained Cxcl1 and Ccl2 mRNAs, but a decrease in mRNA levels of IFNα/β pathway genes as well as Il6, Tnf, and Il1β between days 4 and 6 post infection (p.i.). T cell accumulation and IFNγ production, an essential component of virus control, were not altered. However, IFNγ responsiveness was impaired in microglia/macrophages irrespective of similar pSTAT1 nuclear translocation as in infected controls. The results reveal how perturbation of IFNα/β signaling in neurons can worsen disease course and disrupt complex interactions between the IFNα/β and IFNγ pathways in achieving optimal antiviral responses. IMPORTANCE IFNα/β induction limits CNS viral spread by establishing an antiviral state, but also promotes blood brain barrier integrity, adaptive immunity and microglia/macrophage activation. However, the extent to which glial or neuronal signaling contributes to these diverse IFNα/β functions is poorly understood. Using a neurotropic mouse hepatitis virus encephalomyelitis model this report demonstrates an essential role of IFNα/β receptor 1 (IFNAR1) specifically in neurons to control virus spread, regulate IFNγ signaling, and prevent acute mortality. The results support that effective neuronal IFNAR1 signaling compensates for their low basal expression of genes in the IFNα/β pathway compared to glia. The data further highlight the importance of tightly regulated communication between the IFNα/β and IFNγ signaling pathways to optimize antiviral IFNγ activity.

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Constitutive IFNα/β signaling maintains expression of signaling intermediaries for efficient cytokine responses

Cited by 3 publications

References 61 publications

MicroRNA hsa-miR-203a-3p promotes H1N1 and NDV Virus Replication by suppressing the IFNA signaling

MicroRNA hsa-miR-203a-3p promotes H1N1 and NDV Virus Replication by suppressing the IFNA signaling

A Role of Variance in Interferon Genes to Disease Severity in COVID-19 Patients

Neuronal Ablation of Alpha/Beta Interferon (IFN-α/β) Signaling Exacerbates Central Nervous System Viral Dissemination and Impairs IFN-γ Responsiveness in Microglia/Macrophages

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