The IFN-stimulated gene IFI27 counteracts innate immune responses after viral infections by interfering with RIG-I signaling

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: April 28, 2023

The recognition of viral nucleic acids by host pattern receptors (PRRs) is critical for initiating innate immune responses against infections. These are mediated the induction interferons (IFNs), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines. However, regulatory mechanisms to avoid excessive or long-lasting that may cause detrimental hyperinflammation. Here, we identified a novel function ISG, IFN alpha inducible protein 27 (IFI27) in counteracting triggered cytoplasmic RNA binding. Our model systems included three unrelated infections caused Influenza A virus (IAV), Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), Sendai (SeV), transfection with an analog double-stranded (ds) RNA. Furthermore, found IFI27 has positive effect on IAV SARS-CoV-2 replication, most likely due its ability counteract host-induced antiviral responses, including vivo . We also show interacts PRR retinoic acid-inducible gene I (RIG-I), being interaction RIG-I through Interestingly, our results indicate impairs activation, providing molecular mechanism modulating responses. study identifies explain counterbalancing preventing Therefore, this will have important implications drug design control viral-induced pathology.

Language: Английский

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Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 30, 2023

Interferons (IFNs), IFN-stimulated genes (ISGs), and inflammatory cytokines mediate innate immune responses, are essential to establish an antiviral response. Within the retinoic acid-inducible gene I (RIG-I) is a key sensor of virus infections, mediating transcriptional induction IFNs proteins. Nevertheless, since excessive responses could be detrimental host, these need tightly regulated. In this work, we describe, for first time, how knocking-down or knocking-out expression IFN alpha-inducible protein 6 (IFI6) increases IFN, ISG, pro-inflammatory cytokine after infections with Influenza A Virus (IAV), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Sendai (SeV), poly(I:C) transfection. We also show overexpression IFI6 produces opposite effect, in vitro vivo , indicating that negatively modulates responses. Knocking-out diminishes production infectious IAV SARS-CoV-2, most likely because its effect on Importantly, report novel interaction RIG-I, mediated through binding RNA, affects RIG-I activation, providing molecular mechanism regulating immunity. Remarkably, new functions targeted treat diseases associated exacerbated combat viral such as SARS-CoV-2.

Language: Английский

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Histone deacetylases and their inhibitors in inflammatory diseases

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 179, P. 117295 - 117295

Published: Aug. 14, 2024

Despite considerable research efforts, inflammatory diseases remain a heavy burden on human health, causing significant economic losses annually. Histone deacetylases (HDACs) play role in regulating inflammation (via histone and non-histone protein deacetylation) chromatin structure gene expression regulation. Herein, we present detailed description of the different HDACs their functions analyze diseases, including pro-inflammatory cytokine production reduction, immune cell function modulation, anti-inflammatory activity enhancement. Although HDAC inhibitors have shown broad disease treatment potentials, clinical applicability remains limited because non-specific effects, adverse drug resistance. With further insight, these are expected to become important tools for wide range diseases. This review aims explore mechanisms application prospects multiple

Language: Английский

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Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

MedComm, Journal Year: 2022, Volume and Issue: 3(4)

Published: Sept. 15, 2022

Emerging evidence indicates that resolution of inflammation is a critical and dynamic endogenous process for host tissues defending against external invasive pathogens or internal tissue injury. It has long been known autoimmune diseases chronic inflammatory disorders are characterized by dysregulated immune responses, leading to excessive uncontrol inflammation. The dysregulation epigenetic alterations including DNA methylation, posttranslational modifications histone proteins, noncoding RNA expression implicated in the system. response considered as trigger turn intercede actions. Thus, understanding molecular mechanism dictates outcome targeting regulators disease required resolution. In this article, we elucidate role nuclear factor-κB signaling pathway, JAK/STAT NLRP3 inflammasome diseases. And formulate relationship between inflammation, coronavirus 2019, human cancers. Additionally, review involved innate cells. All matters propose discuss rejuvenation potential interventions target regulatory mechanisms inflammation-associated improve therapeutic outcomes.

Language: Английский

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Targeting SARS-CoV-2 entry processes: The promising potential and future of host-targeted small-molecule inhibitors

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 263, P. 115923 - 115923

Published: Oct. 31, 2023

Language: Английский

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Persistent blood DNA methylation changes one year after SARS-CoV-2 infection

Clinical Epigenetics, Journal Year: 2022, Volume and Issue: 14(1)

Published: July 23, 2022

We recently reported the COVID-19-induced circulating leukocytes DNA methylation profile. Here, we hypothesized that some of these genes would persist differentially methylated after disease resolution. Fifteen participants previously hospitalized for SARS-CoV-2 infection were epityped one year discharge. Of 1505 acute illness-induced regions (DMRs) identified, found 71 with persisted methylated, an average 7 serial CpG positions per DMR. Sixty-four DMRs hypermethylated, and DMR hypomethylated. These data are first evidence changes in endure long recovery from illness.

Language: Английский

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Ganoderma lucidum polysaccharides ameliorate lipopolysaccharide-induced acute pneumonia via inhibiting NRP1-mediated inflammation

Pharmaceutical Biology, Journal Year: 2022, Volume and Issue: 60(1), P. 2201 - 2209

Published: Nov. 14, 2022

Context Ganoderma lucidum polysaccharides (GLP), from (Leyss. ex Fr.) Karst. (Ganodermataceae), are reported to have anti-inflammatory effects, including anti-neuroinflammation and anti-colitis. Nevertheless, the role of GLP in acute pneumonia is unknown.Objective To explore protective against LPS-induced investigate possible mechanisms.Materials methods were extracted used for high-performance liquid chromatography (HPLC) analysis after acid hydrolysis PMP derivatization. Sixty C57BL/6N male mice randomly divided into six groups: Sham, Model, LPS + (25, 50 100 mg/kg/d administered intragastrically two weeks) dexamethasone (6 injected intraperitoneally one week). Acute mouse models established by intratracheal injection LPS. Haematoxylin eosin (H&E) staining was examined evaluate lung lesions. ELISA quantitative real-time PCR employed assess inflammatory factors expression. Western blots carried out measure Neuropilin-1 expression proteins related apoptosis autophagy.Results suppressed cell infiltration. In BALF, counts 1.1 × 106 (model) 7.1 105 (100 mg/kg). Release GM-CSF IL-6 reduced with mg/kg) treatment. The genes IL-1β, IL-6, TNF-α Saa3 reduced. treatment also activation (NRP1), upregulated levels Bcl2/Bax LC3 led downregulation ratio C-Caspase 3/Caspase 3 P62 expression.Discussion conclusions could protect through multiple mechanisms: blocking infiltration cells, inhibiting cytokine secretion, suppressing NRP1 regulating pneumonocyte autophagy.

Language: Английский

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SARS-CoV-2 NSP5 antagonizes MHC II expression by subverting histone deacetylase 2

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(10)

Published: April 29, 2024

ABSTRACT SARS-CoV-2 interferes with antigen presentation by downregulating major histocompatibility complex (MHC) II on antigen-presenting cells, but the mechanism mediating this process is unelucidated. Herein, analysis of protein and gene expression in human cells reveals that MHC downregulated main protease, NSP5. This suppression occurs via decreased regulatory CIITA. CIITA downregulation independent proteolytic activity NSP5, rather, NSP5 delivers HDAC2 to transcription factor IRF3 at an IRF-binding site within promoter. Here, deacetylates inactivates loss prevents further II, alleviated ectopic or knockdown HDAC2. These results identify a which limits expression, thereby delaying weakening subsequent adaptive immune response.

Language: Английский

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Host factor PLAC8 is required for pancreas infection by SARS-CoV-2

Communications Medicine, Journal Year: 2025, Volume and Issue: 5(1)

Published: Feb. 3, 2025

Although COVID-19 initially caused great concern about respiratory symptoms, mounting evidence shows that also the pancreas is productively infected by SARS-CoV-2. However, severity of pancreatic SARS-CoV-2 infection and its pathophysiology still under debate. Here, we investigate consequences role host factor Placenta-associated protein (PLAC8). We analyze plasma levels enzymes inflammatory markers in a retrospective cohort study 120 patients distributed 3 severity-stratified groups. expression PLAC8 deceased as well non-infected donors. perform pseudovirus experiments knock-out PDAC human beta cell-derived cell lines validate results with virus. find analysis circulating aid stratification according to predicts outcomes. Interestingly, an association between postmortem both other bonafide target tissues. Functional demonstrate requirement productive full infectious virus inoculum from Wuhan-1 BA.1 strains. Finally, observe overlap immunoreactivities patients. Our data indicate plausible signs injury required for infection, thus defining new opportunities COVID-19-associated pathogenesis.

Language: Английский

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Understanding the epigenetic mechanisms in SARS CoV-2 infection and potential therapeutic approaches

Virus Research, Journal Year: 2022, Volume and Issue: 318, P. 198853 - 198853

Published: June 28, 2022

Language: Английский

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