Expression Of IFN-stimulated Genes Research Articles

Nailfold videocapillaroscopy findings are associated with IIM subtypes and IFN activation

ObjectiveThis study aimed to characterize nailfold videocapillaroscopy (NVC) features in patients with different subtypes of Idiopathic inflammatory myopathy (IIM) and to investigate the correlations between NVC findings, myositis-specific antibody (MSA) subtypes, disease activity, cytokine profiles, and interferon-stimulated gene (ISG) expression levels.MethodsThis cross-sectional observational single-center study included 55 IIM patients, categorized into MDA5 (+), anti-aminoacyl-tRNA-synthetase antibodies (ARS) (+), and MSA(-) groups based on their MSA profiles. Demographic data, laboratory tests, and NVC assessments were systematically collected and analyzed. The relative expression of type I ISGs in whole blood, as well as serum cytokine and chemokine profiles, were measured. Statistical analyses were performed to explore correlations between NVC scores and clinical parameters, including serum biomarkers.ResultsNVC abnormalities were observed in most IIM patients, with significant differences in NVC features among the MSA subgroups. The MDA5(+) group exhibited significantly higher scores for capillary dilation (P < 0.01), giant capillaries (P < 0.05), microhemorrhages (P < 0.01), and abnormal capillary morphology (P < 0.05) compared to the ARS (+) group. ISG expression and cytokine levels were upregulated in IIM patients, with active disease patients showing significantly higher levels of certain ISGs and cytokines compared to clinically stable patients. Notably, specific NVC score dimensions were positively correlated with the levels of certain ISGs and cytokines. For example, microhemorrhage, capillary dilation, and capillary density all had significantly positive correlations with MX1, IFI27, IP-10, RANTES, and GROα (P < 0.05). And giant capillary is also related to levels of IFI27, SDF-1α, IP-10, RANTES, and GROα (P < 0.05).ConclusionIIM patients exhibit distinct NVC abnormalities, which vary across different MSA subtypes. NVC findings have potential clinical value in screening disease activity and interferon pathway activation in IIM patients.

Induction of LY6E regulates interleukin-1β production, potentially contributing to the immunopathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the deposition of immune complexes (ICs) in various organs, especially the kidney, leading to lupus nephritis, one of the major and therapeutically challenging manifestations of SLE. Among the various cytokines induced in SLE, type I interferons (IFN-Is) play crucial roles in mediating immunopathogenesis, and anti-IFN-I treatment has been approved for SLE treatment. The uptake of ICs by macrophages results in macrophage activation, which initiates, triggers, and exaggerates immune responses in SLE. After observing the induction of an IFN-stimulated gene, LY6E, in monocytes from SLE patients, we demonstrated the colocalization of both LY6E and a macrophage marker in kidneys from pristane-induced lupus-prone mice and from patients with lupus nephritis. By studying mouse bone marrow-derived macrophages, we showed that LY6E regulated IFN-α- and IC-induced production and secretion of mature interleukin-1β (mIL-1β), foam cell formation and several mitochondria-associated mechanisms, such as the release of mitochondrial DNA (mtDNA) but not mitochondrial RNA (mtRNA) into the cytosol, the generation of mitochondrial reactive oxygen species (mtROS) and ROS, the activation of caspase 1, NLRP3, and the stimulator of interferon genes (STING) signaling pathway, and the activation of cytidine/uridine monophosphate kinase 2 (CMPK2), which were involved in LY6E-mediated immunomodulatory effects. In addition, synergistic effects of a combination of IL-1β and IFN-α and of IL-1β and ICs on the induction of the expression of IFN-stimulated genes were observed. In addition to revealing the proinflammatory roles and mechanisms of LY6E in macrophages, given that various subgroups of macrophages have been identified in the kidneys of patients with lupus nephritis, targeted treatment aimed at LY6E may be a potential therapeutic for lupus nephritis.

Interferon Regulatory Factor 3 Exacerbates the Severity of COVID-19 in Mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019, causing the COVID-19 pandemic. While most infected people experienced mild illness, others progressed to severe disease, characterized by hyperinflammation and respiratory distress. There is still much to learn about the innate immune response to this virus. Interferon regulatory factor 3 (IRF3) is a transcription factor that is activated when pattern recognition receptors detect viruses. Upon activation, IRF3 induces the expression of interferon beta (IFN-β) and interferon-stimulated genes, which protect the host from viral infection. However, coronaviruses antagonize this pathway, delaying type 1 IFN production. It is, therefore, unclear how IRF3 influences COVID-19 disease. Our prior reports showed that IRF3 promotes harmful inflammation during bacterial sepsis in mice. We hypothesized that IRF3 cannot effectively control the SARS-CoV-2 viral load and instead promotes harmful inflammation during severe COVID-19. We used mice transgenic for the human angiotensin converting-enzyme 2 transgene, driven by the keratin 18 promoter (K18-ACE2 mice) that were IRF3 deficient or IRF3 sufficient to test how IRF3 influences COVID-19 disease. Upon infection with SARS-CoV-2, K18-ACE2 mice showed a dose-dependent disease, characterized by mortality, lethargy, weight loss, and lung pathology, reminiscent of clinical COVID-19. However, K18-ACE2 mice lacking IRF3 were protected from severe disease with reduced mortality (84.6% vs. 100%) and disease score. We found that IRF3 promoted IFN-β production in the lungs and reprogrammed the cytokine profile, while viral load in the lungs was similar in the presence or absence of IRF3. These data indicated that IRF3 played a detrimental role in murine COVID-19 associated with changes in IFN-β and inflammatory cytokines.

Molecular glues that inhibit deubiquitylase activity and inflammatory signaling.

Deubiquitylases (DUBs) are crucial in cell signaling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signaling by cleaving K63-linked polyubiquitin chains on type I interferon receptors (IFNAR1). As a Zn2+-dependent JAMM/MPN (JAB1, MOV34, MPR1, Pad1 N-terminal) DUB, BRCC36 is challenging to target with selective inhibitors. Here, we discover first-in-class inhibitors, termed BRISC molecular glues (BLUEs), which stabilize a 16-subunit human BRISC dimer in an autoinhibited conformation, blocking active sites and interactions with the targeting subunit, serine hydroxymethyltransferase 2. This unique mode of action results in selective inhibition of BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. BLUE treatment reduced interferon-stimulated gene expression in cells containing wild-type BRISC and this effect was abolished when using structure-guided, inhibitor-resistant BRISC mutants. Additionally, BLUEs increase IFNAR1 ubiquitylation and decrease IFNAR1 surface levels, offering a potential strategy to mitigate type I interferon-mediated diseases. Our approach also provides a template for designing selective inhibitors of large protein complexes by promoting rather than blocking protein-protein interactions.

Mpox virus poxin-schlafen fusion protein suppresses innate antiviral response by sequestering STAT2

ABSTRACT Mpox virus (MPXV) has to establish efficient interferon (IFN) antagonism for effective replication. MPXV-encoded IFN antagonists have not been fully elucidated. In this study, the IFN antagonism of poxin-schlafen (PoxS) fusion gene of MPXV was characterized. MPXV PoxS was capable of decreasing cGAS-produced 2′3′-cGAMP, like its ortholog poxin of vaccinia virus, which is the first known cytosolic nuclease that hydrolyzes the 3′-5′ bond of 2′3′-cyclic GMP-AMP (cGAMP). However, MPXV PoxS did not suppress cGAS-STING-mediated type I IFN production. Instead, MPXV PoxS antagonized basal and type I IFN-induced expression of IFN-stimulated genes such as OAS1, SAMD9, SAMD9L, ISG15, ISG56 and IFIT3. Consistently, MPXV PoxS inhibited both basal and type I IFN-stimulated activity of interferon-stimulated response elements, but did not affect activation of IFN-γ-activated sites. Mechanistically, MPXV PoxS interacted with STAT2 and sequestered it in the cytoplasm. Both the viral schlafen fusion and the active site of 2′3′-cGAMP nuclease were required for STAT2 sequestration and consequent suppression of IFN-stimulated gene expression. MPXV PoxS conferred resistance to the suppression of MPXV replication by type I IFN. Taken together, our findings suggested that MPXV PoxS counteracts host antiviral response by sequestering STAT2 to circumvent basal and type I IFN-induced expression of antiviral genes.

Identification of an IRF8 gene in common carp (Cyprinus carpio. L) and its regulatory role in immune responses

BackgroundInterferon (IFN) regulatory factors (IRF) are the crucial transcription factors for IFN expression and leading host cells response to viral infection. IRF8 in mammals plays vital roles in the innate and adaptive immune systems. In this study, we identified and characterized the common carp (Cyprinus carpio. L) IRF8 gene (ccIRF8) to further clarify the function of IRF8 in teleost fish.ResultsThe complete cDNA sequence of ccIRF8 was 1431 bp and encodes a polypeptide of 431 amino acids. Analysis of the putative amino acid sequence showed that ccIRF8 encodes structures typical of the IRF family, including a DNA-binding domain (DBD), an IRF-association domain (IAD) and two nuclear localization signals (NLS). Comparison with homologous proteins showed that the deduced protein has the highest sequence identity to grass carp IRF8 (92.7%). Phylogenetic analysis grouped ccIRF8 with other IRF8s of teleosts. Quantitative RT-PCR analysis showed that ccIRF8 transcripts were detectable in all investigated tissues of healthy fish with the highest level in spleen. Following poly I: C and Aeromonas hydrophila challenge, ccIRF8 transcripts were induced significantly in immune relevant tissues. In addition, ccIRF8 was induced by poly I: C and ipopolysaccharide (LPS), peptidoglycan (PGN) and flagellin in HKLs. Overexpression of ccIRF8 increased the expression of IFN and IFN-stimulated genes (ISGs), and a dual-luciferase reporter assay revealed that ccIRF8 decreased the activation of NF-κB though TRAF6.ConclusionsOverall, our findings provide a new perspective on the role of IRF8 in innate immunity in fish, as well as insights that will help the prevention and control of disease in the common carp farming industry.

The role of type I interferon signaling in myeloid anti-tumor immunity.

Tumors often arise in chronically inflamed, and thus immunologically highly active niches. While immune cells are able to recognize and remove transformed cells, tumors eventually escape the control of the immune system by shaping their immediate microenvironment. In this context, macrophages are of major importance, as they initially exert anti-tumor functions before they adopt a tumor-associated phenotype that instead inhibits anti-tumor immune responses and even allows for sustaining a smoldering inflammatory, growth promoting tumor microenvironment (TME). Type I interferons (IFNs) are well established modulators of inflammatory reactions. While they have been shown to directly inhibit tumor growth, there is accumulating evidence that they also play an important role in altering immune cell functions within the TME. In the present review, we focus on the impact of type I IFNs on anti-tumor responses, driven by monocytes and macrophages. Specifically, we will provide an overview of tumor-intrinsic factors, which impinge on IFN-stimulated gene (ISG) expression, like the presence of nucleic acids, metabolites, or hypoxia. We will further summarize the current understanding of the consequences of altered IFN responses on macrophage phenotypes, i.e., differentiation, polarization, and functions. For the latter, we will focus on macrophage-mediated tumor cell killing and phagocytosis, as well as on how macrophages affect their environment by secreting cytokines and directly interacting with immune cells. Finally, we will discuss how type I IFN responses in macrophages might affect and should be considered for current and future tumor therapies.

Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series.

Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series.

Identified genetic locus for longitudinal disease activity in adults with systemic lupus erythematosus.

Genetics significantly impact systemic lupus erythematosus (SLE) risk, disease manifestations, and damage. Our aim was to identify genetic risk loci for disease activity burden over time. We included participants from a tertiary care Lupus Clinic. Participants met ACR and/or SLICC classification criteria for SLE, were genotyped on one of three arrays, and had > =3 measures of disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) to derive adjusted mean SLEDAI-2K and glucocorticoid scores (AMSG). We completed a genome-wide association study (GWAS) of AMSG, adjusted for sex and 5 PCs, and stratified by array, then meta-analyzed GWAS (P < 5x10-8). Meta-GWAS results were used in colocalization analyses with expression quantitative trait loci in multiple tissues. In a subset of patients, we examined the association between the top SNP for AMSG and interferon-stimulated gene expression. The cohort included 538 individuals with SLE (88% female), with a median age at diagnosis of 30.7 years (IQR = 23.3, 41.7 years). Most patients (75%) had a first clinic visit within 1 year of SLE diagnosis and were followed for a mean of 4.5 years (SD = 0.95). The median AMSG was 5.5 (Q25, Q75 = 3.2,8.8). Meta-GWAS identified a genome-wide significant SNP for AMSG (rs4561613) on chromosome 2, intronic to AGAP1 (Beta = 0.34, SE = 0.06, p = 4.16x1 0 -9). Colocalization analysis did not identify a significant difference in gene expression for the top SNP. Interferon gene scores were significantly associated with AMSG (Beta = 0.02, SE = 8.70x10-3, p = 0.006). We identified a genome-wide significant locus intronic to AGAP1 for SLE disease activity burden as measured by AMSG.

Abstract A062: Mechanisms mediating hypoxic memory of type I IFN signaling suppression and implications for immune evasion in luminal breast cancer cells

Abstract Prevention of metastases is critical for the future of breast cancer research, as metastatic cancer is extremely difficult to manage and treat. Solid tumors often contain patches of hypoxic regions that yield aggressive, pro-metastatic phenotypes. Recent work in our lab has shown that long-term hypoxia suppresses type I interferon (IFN) signaling in breast cancer cells, and this suppression of IFN signaling is maintained even after reoxygenation, indicative of “hypoxic memory.” Breast cancer cells and circulating tumor cells (CTCs) that have exited hypoxia but maintain such hypoxic memory showed enhanced metastatic potential. In addition to tumor intrinsic effects, IFN suppression can dampen surrounding immune cell populations within the tumor microenvironment, primarily through interferon-stimulated genes (ISGs) which carry out immune functions through activation of various immune cell populations. More research is needed to understand how ISGs are downregulated in hypoxia and how those changes in gene expression contribute to immunosuppressive ability of hypoxic and post-hypoxic cells. Interferon-inducible 44-like (IFI44L) is an ISG that has been associated with tumor-infiltrating lymphocytes and enhanced metastasis in other cancers, but its role in breast cancer has not been studied. We found that IFI44L is significantly suppressed in breast cancer cells in hypoxia and maintained after reoxygenation as hypoxic memory. Overexpressing interferon regulatory factors (IRFs), which are positive regulators of the type I IFN pathway, did not rescue hypoxic suppression and memory of IFI44L, suggesting IRFs are not the sole regulator of IFN and ISG expression in hypoxia. Current experiments in the lab are ongoing to address the mechanisms responsible for hypoxic memory of IFI44L suppression. Additionally, co-culture studies of IFI44L knockdown and overexpression breast cancer cell lines with different immune populations will shed light on the role of hypoxic suppression of IFI44L in immune evasion. To better understand implications of maintained IFI44L suppression, we will also examine immune cell activity and metastatic potential using in vivo mouse studies. We expect to see less immune cell effect and enhanced metastasis with IFI44L knockdown and reversed phenotypes with overexpression of IFI44L. Understanding mechanisms of immune suppression and evasion mediated via IFI44L can lead to strategies for targeting hypoxia-mediated tumorigenesis and metastasis. Citation Format: Rebecca Marker, Aidan Moriarty, Remi Klotz, Min Yu. Mechanisms mediating hypoxic memory of type I IFN signaling suppression and implications for immune evasion in luminal breast cancer cells [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A062.

3-D Sustained-Release Culture Carrier Alleviates Rat Intervertebral Disc Degeneration by Targeting STING in Transplanted Skeletal Stem Cells.

The hypoxic and high-pressure microenvironment of the intervertebral discs poses a major challenge to the survival and therapeutic efficiency of exogenous stem cells. Therefore, improving the utilization efficiency and therapeutic effect of exogenous stem cells to delay intervertebral disc degeneration (IVDD) is of great importance. Here, hypoxic induction studies are conducted in vivo and in vitro using rat costal cartilage-derived skeletal stem cells (SSCs) and find that hypoxia activates the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway and increased reactive oxygen species (ROS) accumulation, triggering ferroptosis in SSCs through hypoxia-inducible factor-1 alpha-dependent mitophagy. Progressive hypoxia preconditioning reduce STING expression and ROS accumulation, inducing SSCs differentiation into nucleus pulposus-like cells via the Wnt signaling pathway. Considering this, a 3-D sustained-release culture carrier is generated by mixing SSCs with methacrylated hyaluronic acid and polydopamine nanoparticles coated with the STING inhibitor C-176 and evaluated its inhibitory effect on IVDD. This carrier is demonstrated to inhibit the cGAS/STING pathway and prevent ROS accumulation by continuously releasing C-176-coated polydopamine nanoparticles, thereby reducing ferroptosis, promoting differentiation, and ultimately attenuating IVDD, suggesting its potential as a novel treatment strategy.

Silybin attenuates microglia-mediated neuroinflammation via inhibition of STING in experimental subarachnoid hemorrhage.

Silybin attenuates microglia-mediated neuroinflammation via inhibition of STING in experimental subarachnoid hemorrhage.

A non-structural protein 1 substitution of dengue virus enhances viral replication by interfering with the antiviral signaling pathway

BackgroundThe largest dengue virus 2 (DENV2) outbreak occurred in Taiwan in 2015, resulting in many fatalities. We therefore aim to identify crucial genetic variations which determine the virulence of the 2015 Taiwan outbreak strains.MethodsWe compared the 2015 Taiwan DENV2 sequences to the pre-2015 sequences. Reverse genetics (rg) viruses with substitutions were produced and the viral growth kinetics were investigated. We treated A549 cells with interferon (IFN) to determine the interferon-stimulated genes (ISGs) expression and STAT1 phosphorylation in the rg viral infection and plasmid transfection systems. IFN and pro-inflammatory cytokines levels were measured upon DENV infection using ELISA.ResultsThe rgNS1-K272R mutant showed faster replication in IFN-I producing cells compared to wildtype (WT) virus. Results revealed that NS1-K272R substitution contributed to higher soluble NS1 secretion and evade the antiviral response by suppressing the expression of ISGs and STAT1 phosphorylation compared to NS1-WT. Infection with rgNS1-K272R induced higher secretion of pro-inflammatory cytokines through the activation of canonical nuclear factor-kappa B (NF-κB) signaling pathway.ConclusionsOur results revealed that the DENV NS1 amino acid substitution affects the NS1 ability in immune evasion, which may contribute to the largest dengue outbreak in Taiwan since the 1990s.

Intrinsic STING of CD8 + T cells regulates self-metabolic reprogramming and memory to exert anti-tumor effects

BackgroundOur team has previously found that the stimulator of interferon genes (STING) plays a more significant anti-tumor role in host immune cells than in tumor cells. Although STING is necessary for CD8 + T cells to exert immunological activity, its effect on CD8 + T cells remains debatable. In this study, we used both in vitro and in vivo models to explore the metabolic effects of STING on CD8 + T cells.MethodsPeripheral blood lymphocytes were procured from non-small cell lung cancer (NSCLC) patients receiving anti-PD-1 therapy to investigate the correlation between STING expression levels, CD8 + T-cell subsets, and immunotherapy efficacy. STING knockout (STING-KO) mice were used for in vivo studies. RNA-seq, seahorse, flow cytometry, electron microscopy, qPCR, immunofluorescence, western blotting, and immunoprecipitation were performed to explore the underlying mechanisms of STING in regulating CD8 + T cell function.ResultsWe discovered that the expression level of STING in immune cells exhibited a significant correlation with immunotherapy efficacy, as well as with the proportion of central memory CD8 + T cells. Moreover, we found that the loss of the STING gene results in a reduction in the number of mitochondria and a change in the metabolic pathway selection, thereby inducing excessive glycolysis in CD8 + T cells. This excessive glycolysis generates high levels of lactate, which further inhibits IFN-γ secretion and impacts memory T cell differentiation. Correcting the glycolysis disorder partially restored function and IFN-γ secretion, rescued the central memory CD8 + T subset, and improved immunotherapy in STING-KO mice. This provides a new treatment strategy for patients with low STING expression and a poor response to immunotherapy.ConclusionIntrinsic STING of CD8 + T cells affects their function through the HK2/Lactate/IFN-γ axis and affects memory differentiation by regulating glycolysis.

Activation of the tumor cell-intrinsic STING pathway induced by Fusobacterium nucleatum is associated with poor prognosis in esophageal cancer patients.

Intratumoral Fusobacterium nucleatum (Fn) infection is closely associated with poor prognosis in esophageal cancer (EC) due to its impact on the tumor microenvironment (TME). The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is critical for regulating immune cell activation in the TME. However, the link between intratumoral Fn infection and the activation of the cGAS-STING pathway in tumor cells, as well as its effects on EC progression, remains largely unknown. In the present study, we investigated the impact of intratumoral Fn infection on the activation of the tumor cell-intrinsic cGAS-STING pathway and EC progression by analyzing our own EC cohort and performing in vitro experiments using co-cultures of EC-cell lines and Fn. The expression of tumor cell-intrinsic STING was significantly associated with worse prognosis in Fn-high EC patients. Exposure to Fn significantly activated the STING pathway in EC cells. RNA-seq analysis revealed that exposure to Fn markedly activated cytokine-chemokine-related signaling pathways and induced the expression of several cytokines and chemokines in STING-expressing EC cells. Among the differentially expressed cytokine and chemokine genes in EC cells co-cultured with Fn, analysis of TCGA datasets demonstrated that the expression of CCL20, CXCL10, and CSF2 may be associated with poor prognosis in EC patients. We revealed that the activation of the STING signaling pathway and the subsequent expression of cytokines and chemokines in EC cells induced by Fn infection may be closely associated with poor prognosis in EC patients.

Critical role of Oas1g and STAT1 pathways in neuroinflammation: insights for Alzheimer’s disease therapeutics

BackgroundAlzheimer’s disease (AD) has a significant impact on an individual’s health and places a heavy burden on society. Studies have emphasized the importance of microglia in the progression and development of AD. Interferon responses and Interferon-stimulated genes (ISGs) significantly function in neuroinflammatory and neurodegenerative diseases involving AD. Therefore, further exploration of the relationship among microglia, ISGs, and neuroinflammation in AD is warranted.MethodsMicroglia datasets from the GEO database were retrieved, along with additional microglia RNA-seq data from laboratory mice. Weighted Correlation Network Analysis was used on the training dataset to identify gene co-expression networks. Genes from the black module were intersected with interferon-stimulated genes, and differentially expressed genes (DEGs) were identified. Machine learning algorithms were applied to DEGs, and genes selected by both methods were identified as hub genes, with ROC curves used to evaluate their diagnostic accuracy. Gene Set Enrichment Analysis was performed to reveal functional pathways closely relating to hub genes. Microglia cells were transfected with siRNAs targeting Oas1g and STAT1. Total RNA from microglia cells and mouse brain tissues was extracted, reverse-transcribed, and analyzed via qRT-PCR. Proteins were extracted from cells, quantified, separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies. Microglia cells were fixed, permeabilized, blocked, and stained with antibodies for STAT1, then visualized and photographed.ResultsBioinformatics and machine learning algorithms revealed that Oas1g was identified as a hub gene, with an AUC of 0.812. Enrichment Analysis revealed that Oas1g is closely associated with interferon-related pathways. Expression of Oas1g was validated in AD mouse models, where it was significantly upregulated after microglial activation. Knockdown experiments suggested siOas1g attenuated the effect of siSTAT1, and the expressions of STAT1 and p-STAT1 were elevated. siOas1g could reverse the effect of siSTAT1, indicating that Oas1g potentially regulates the ISGs through the STAT1 pathway.ConclusionWe demonstrated that Oas1g was identified as a hub ISG in AD and can downregulate the activation of IFN-β and STAT1, reducing the expression of ISGs in neuroinflammation. Oas1g might potentially be a beneficial candidate for both prevention and treatment of AD.

Prognostic Impact of Stimulator of Interferon Genes Expression in Triple Negative Breast Cancer.

Patients with triple negative breast cancer (TNBC) who have a poor response to neoadjuvant chemotherapy (NAC) have worse survival and new treatment strategies need to be developed. TNBC is considered a subtype in which the cyclic GMP-AMP synthase (cGAS) is linked to the stimulator of interferon genes (STING) pathway, an innate immune response that recognizes cytosolic nucleic acid components, is activated when DNA damage occurs, and is attracting attention as a new therapeutic target. Patients with TNBC who underwent surgery following NAC and for whom pre- and post-treatment tissue specimens were available were enrolled in this study. To examine the association of STING expression with immune profiles and prognosis, STING, cGAS, CD8, and programmed cell death ligand 1 (PD-L1) expressions in tumor cells (TCs) and immune cells (ICs), and tumor infiltrating lymphocytes (TILs) were assessed using immunohistochemistry of specimens obtained at pre-treatment and at surgery. Ninety-one cases were eligible, of which 68 cases were evaluable and included in the analysis. The high STING expression at baseline was marginally correlated with TILs, but not with CD8+ cells or PD-L1 expression. Patients with sustained high expression of STING before and after NAC had a significantly poorer prognosis than that of others for distant recurrence-free survival and breast cancer-specific survival independent of nodal status, lymphatic invasion and therapeutic effects (p = 0.024 and 0.014, respectively). TNBCs with sustained high STING expression following NAC demonstrated a poor prognosis and will be a target for new treatment strategies.

Signaling pathways of duck RIG-I in gene-edited DF1 chicken cells.

Signaling pathways of duck RIG-I in gene-edited DF1 chicken cells.

Single-cell RNA sequencing reveals intrahepatic signature related to pathobiology of duck hepatitis A virus type 3 (DHAV-3) infection.

Single-cell RNA sequencing reveals intrahepatic signature related to pathobiology of duck hepatitis A virus type 3 (DHAV-3) infection.

Variants and vaccines impact nasal immunity over three waves of SARS-CoV-2.

Viral variant and host vaccination status impact infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet how these factors shift cellular responses in the human nasal mucosa remains uncharacterized. We performed single-cell RNA sequencing (scRNA-seq) on nasopharyngeal swabs from vaccinated and unvaccinated adults with acute Delta and Omicron SARS-CoV-2 infections and integrated with data from acute infections with ancestral SARS-CoV-2. Patients with Delta and Omicron exhibited greater similarity in nasal cell composition driven by myeloid, T cell and SARS-CoV-2hi cell subsets, which was distinct from that of ancestral cases. Delta-infected samples had a marked increase in viral RNA, and a subset of PER2+EGR1+GDF15+ epithelial cells was enriched in SARS-CoV-2 RNA+ cells in all variants. Prior vaccination was associated with increased frequency and activation of nasal macrophages. Expression of interferon-stimulated genes negatively correlated with coronavirus disease 2019 (COVID-19) severity in patients with ancestral and Delta but not Omicron variants. Our study defines nasal cell responses and signatures of disease severity across SARS-CoV-2 variants and vaccination.