A Guideline Strategy for Identifying Genes/Proteins Regulating Antiviral Innate Immunity.

Antiviral innate immunity is a complicated system initiated by the induction of type I interferon (IFN-I) and downstream interferon-stimulated genes (ISGs) and is finely regulated by numerous positive and negative factors at different signaling adaptors. During this process, posttranslational modifications, especially ubiquitination, are the most common regulatory strategy used by the host to switch the antiviral innate signaling pathway and are mainly controlled by E3 ubiquitin ligases from different protein families. A comprehensive understanding of the regulatory mechanisms and a novel discovery of regulatory factors involved in the IFN-I signaling pathway are important for researchers to identify novel therapeutic targets against viral infectious diseases based on innate immunotherapy. In this section, we use the E3 ubiquitin ligase as an example to guide the identification of a protein belonging to the RING Finger (RNF) family that regulates the RIG-I-mediated IFN-I pathway through ubiquitination.

Varicella-zoster virus recapitulates its immune evasive behaviour in matured hiPSC-derived neurospheroids.

Varicella-zoster virus (VZV) encephalitis and meningitis are potential central nervous system (CNS) complications following primary VZV infection or reactivation. With Type-I interferon (IFN) signalling being an important first line cellular defence mechanism against VZV infection by the peripheral tissues, we here investigated the triggering of innate immune responses in a human neural-like environment. For this, we established and characterised 5-month matured hiPSC-derived neurospheroids (NSPHs) containing neurons and astrocytes. Subsequently, NSPHs were infected with reporter strains of VZV (VZVeGFP-ORF23) or Sendai virus (SeVeGFP), with the latter serving as an immune-activating positive control. Live cell and immunocytochemical analyses demonstrated VZVeGFP-ORF23 infection throughout the NSPHs, while SeVeGFP infection was limited to the outer NSPH border. Next, NanoString digital transcriptomics revealed that SeVeGFP-infected NSPHs activated a clear Type-I IFN response, while this was not the case in VZVeGFP-ORF23-infected NSPHs. Moreover, the latter displayed a strong suppression of genes related to IFN signalling and antigen presentation, as further demonstrated by suppression of IL-6 and CXCL10 production, failure to upregulate Type-I IFN activated anti-viral proteins (Mx1, IFIT2 and ISG15), as well as reduced expression of CD74, a key-protein in the MHC class II antigen presentation pathway. Finally, even though VZVeGFP-ORF23-infection seems to be immunologically ignored in NSPHs, its presence does result in the formation of stress granules upon long-term infection, as well as disruption of cellular integrity within the infected NSPHs. Concluding, in this study we demonstrate that 5-month matured hiPSC-derived NSPHs display functional innate immune reactivity towards SeV infection, and have the capacity to recapitulate the strong immune evasive behaviour towards VZV.

Protein kinase R induced by type I interferons is a main regulator of reactive microglia in Zika virus infection.

Microglial cells are the phagocytic cells of the brain that under physiological conditions participate in brain homeostasis and surveillance. Under pathogenic states, microglia undergoes strong morphological and transcriptional changes potentially leading to sustained neuroinflammation, brain damage, and cognitive disorders. Postnatal and adult Zika virus (ZIKV) brain infection is characterized by the induction of reactive microglia associated with brain inflammation, synapse loss and neuropathogenesis. Contrary to neurons, microglial cells are not infected by ZIKV thus raising the question of the mechanism governing ZIKV-induced microglia's reactivity. In this work, we have questioned the role of exogenous, neuronal type I interferons (IFNs-I) in regulating ZIKV-induced microglia's reactivity. Primary cultured microglial cells were either treated with conditioned media from ZIKV-infected mature neurons or co-cultured with ZIKV-infected neurons. Using either an antibody directed against the IFNAR receptor that neutralizes the IFNs-I response or Ifnar-/-microglial cells, we demonstrate that IFNs-I produced by ZIKV-infected neurons are the main regulators of the phagocytic capacity and the pro-inflammatory gene expression profile of reactive, non-infected microglial cells. We identify protein kinase R (PKR), whose expression is activated by IFNs-I, as a major regulator of the phagocytic capacity, pro-inflammatory response, and morphological changes of microglia induced by IFNs-I while up-regulating STAT1 phosphorylation and IRF1 expression. Results obtained herein in vitro with primary cultured cells and in vivo in ZIKV-infected adult immunocompetent mice, unravel a role for IFNs-I and PKR in directly regulating microglia's reactivity that could be at work in other infectious and non-infectious brain pathologies.

Exploring genetic and immune cell dynamics in systemic lupus erythematosus patients with Epstein-Barr virus infection via machine learning.

OBJECTIVES: Epstein-Barr Virus (EBV) is a widespread virus implicated in various diseases, including Systemic Lupus Erythematosus (SLE). However, the specific genes and pathways altered in SLE patients with EBV infection remain unclear. We aimed to identify key genes and immune cells in SLE patients with EBV infection. METHODS: The datasets of SLE (GSE50772 and GSE81622) or EBV infection (GSE85599 and GSE45918) were obtained from the Gene Expression Omnibus (GEO) database. Next, differential gene expression (DEGs) analysis were conducted to identify overlapping DEGs and then enrichment analysis was performed. Machine learning was applied to identify key genes. Validation was conducted using ROC curve analysis and expression level verification in test datasets and single-cell RNA sequencing. Immune cell infiltration patterns were analyzed using CIBERSORTx, and clinical data were reviewed for SLE patients. RESULTS: We identified 58 overlapping DEGs enriched in interferon-related pathways. Five overlapping DEGs (IFI27, TXK, RAPGEF6, PIK3IP1, PSENEN) were selected as key genes by machine learning algorithms, with IFI27 showing the highest diagnostic performance. The expression level of IFI27 was found higher in CD4 CTL, CD8 naïve and various B cell subsets of SLE patients with EBV infection. IFI27 showed significant correlation with B intermediate and CD4 CT. Clinical data showed lower CD4 T cell proportions in SLE patients with EBV infection. CONCLUSION: This study identifies IFI27 as a key gene for SLE patients with EBV infection, influencing CD4 CTL and B cell subtypes. These findings enhance the understanding of the molecular mechanisms linking SLE and EBV infection, providing potential targets for diagnostic and therapeutic strategies.

Stress triggers irritable bowel syndrome with diarrhea through a spermidine-mediated decline in type I interferon.

Irritable bowel syndrome with diarrhea (IBS-D) is a common and chronic gastrointestinal disorder that is characterized by abdominal discomfort and occasional diarrhea. The pathogenesis of IBS-D is thought to be related to a combination of factors, including psychological stress, abnormal muscle contractions, and inflammation and disorder of the gut microbiome. However, there is still a lack of comprehensive analysis of the logical regulatory correlation among these factors. In this study, we found that stress induced hyperproduction of xanthine and altered the abundance and metabolic characteristics of Lactobacillus murinus in the gut. Lactobacillus murinus-derived spermidine suppressed the basal expression of type I interferon (IFN)-α in plasmacytoid dendritic cells by inhibiting the K63-linked polyubiquitination of TRAF3. The reduction in IFN-α unrestricted the contractile function of colonic smooth muscle cells, resulting in an increase in bowel movement. Our findings provided a theoretical basis for the pathological mechanism of, and new drug targets for, stress-exposed IBS-D.

Type I IFN drives unconventional IL-1ß secretion in lupus monocytes.

Opsonization of red blood cells that retain mitochondria (Mito+ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1ß (mIL-1ß) upon Mito+ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors' (RLRs) sensing of Mito+ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1ß (IL-1ß) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito+ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1ß secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1ß into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1ß and expanded in SLE patients with active disease.

A combination of major histocompatibility complex (MHC) I overexpression and type I interferon induce mitochondrial dysfunction in human skeletal myoblasts.

The overexpression of major histocompatibility complex (MHC) I on the surface of muscle fibers is a characteristic hallmark of the idiopathic inflammatory myopathies (IIMs), collectively termed myositis. Alongside MHC-I overexpression, subtypes of myositis, display a distinct type I interferon (IFN) signature. This study examined the combinational effects of elevated MHC-I and type I IFNs (IFNα/ß) on mitochondrial function, as mitochondrial dysfunction is often seen in IIMs. Human skeletal muscle myoblasts were transfected with an MHC-I isoform using the mammalian HLA-A2/Kb vector. Mitochondrial respiration, mitochondrial membrane potential, and reactive oxygen/nitrogen species generation were assessed with or without IFNα and IFNß. We show that MHC-I overexpression in human skeletal muscle myoblasts led to decreased basal glycolysis and mitochondrial respiration, cellular spare respiratory capacity, adenosine triphosphate-linked respiration, and an increased proton leak, which were all exaggerated by type I IFNs. Mitochondrial membrane depolarization was induced by MHC-I overexpression both in absence and presence of type I IFNs. Human myoblasts overexpressing MHC-I showed elevated nitric oxide generation that was abolished when combined with IFN. MHC-I on its own did not result in an increased reactive oxygen species (ROS) production, but IFN on their own, or combined with MHC-I overexpression did induce elevated ROS generation. Surprisingly, we observed no gross changes in mitochondrial reticular structure or markers of mitochondrial dynamics. We present new evidence that MHC-I overexpression and type I IFNs aggravate the effects each has on mitochondrial function in human skeletal muscle cells, providing novel insights into their mechanisms of action and suggesting important implications in the further study of myositis pathogenesis.

Type I Interferonopathy among Non-Elderly Female Patients with Post-Acute Sequelae of COVID-19.

The pathophysiological mechanisms of the post-acute sequelae of COVID-19 (PASC) remain unclear. Sex differences not only exist in the disease severity of acute SARS-CoV-2 infection but also in the risk of suffering from PASC. Women have a higher risk of suffering from PASC and a longer time to resolution than men. To explore the possible immune mechanisms of PASC among non-elderly females, we mined single-cell transcriptome data from peripheral blood samples of non-elderly female patients with PASC and acute SARS-CoV-2 infection, together with age- and gender-matched non-PASC and healthy controls available from the Gene Expression Omnibus database. By comparing the differences, we found that a CD14+ monocyte subset characterized by higher expression of signal transducers and activators of transcription 2 (STAT2) (CD14+STAT2high) was notably increased in the PASC patients compared with the non-PASC individuals. The transcriptional factor (TF) activity analysis revealed that STAT2 and IRF9 were the key TFs determining the function of CD14+STAT2high monocytes. STAT2 and IRF9 are TFs exclusively involving type I and III interferon (IFN) signaling pathways, resulting in uncontrolled IFN-I signaling activation and type I interferonopathy. Furthermore, increased expression of common interferon-stimulated genes (ISGs) has also been identified in most monocyte subsets among the non-elderly female PASC patients, including IFI6, IFITM3, IFI44L, IFI44, EPSTI1, ISG15, and MX1. This study reveals a featured CD14+STAT2high monocyte associated with uncontrolled IFN-I signaling activation, which is indicative of a possible type I interferonopathy in the non-elderly female patients with PASC.

Global RNA Interaction and Transcriptome Profiles Demonstrate the Potential Anti-Oncogenic Targets and Pathways of RBM6 in HeLa Cells.

BACKGROUND: The fate and functions of RNAs are coordinately regulated by RNA-binding proteins (RBPs), which are often dysregulated in various cancers. Known as a splicing regulator, RNA-binding motif protein 6 (RBM6) harbors tumor-suppressor activity in many cancers; however, there is a lack of research on the molecular targets and regulatory mechanisms of RBM6. METHODS: In this study, we constructed an RBM6 knock-down (shRBM6) model in the HeLa cell line to investigate its functions and molecular targets. Then we applied improved RNA immunoprecipitation coupled with sequencing (iRIP-seq) and whole transcriptome sequencing approaches to investigate the potential role and RNA targets of RBM6. RESULTS: Using The Cancer Genome Atlas dataset, we found that higher expression of RBM6 is associated with a better prognosis in many cancer types. In addition, we found that RBM6 knockdown promoted cell proliferation and inhibited apoptosis, demonstrating that RBM6 may act as an anti-oncogenic protein in cancer cells. RBM6 can regulate the alternative splicing (AS) of genes involved in DNA damage response, proliferation, and apoptosis-associated pathways. Meanwhile, RBM6 knockdown activated type I interferon signaling pathways and inhibited the expression of genes involved in the cell cycle, cellular responses to DNA damage, and DNA repair pathways. The differentially expressed genes (DEGs) by shRBM6 and their involved pathways were likely regulated by the transcription factors undergoing aberrant AS by RBM6 knockdown. For iRIP-seq analysis, we found that RBM6 could interact with a large number of mRNAs, with a tendency for binding motifs GGCGAUG and CUCU. RBM6 bound to the mRNA of cell proliferation- and apoptosis-associated genes with dysregulated AS after RBM6 knockdown. CONCLUSIONS: In summary, our study highlights the important role of RBM6, as well as the downstream targets and regulated pathways, suggesting the potential regulatory mechanisms of RBM6 in the development of cancer.

Whole-transcriptome analyses of ovine lung microvascular endothelial cells infected with bluetongue virus.

Bluetongue virus (BTV) infection induces profound and intricate changes in the transcriptional profile of the host to facilitate its survival and replication. However, there have been no whole-transcriptome studies on ovine lung microvascular endothelial cells (OLMECs) infected with BTV. In this study, we comprehensively analysed the whole-transcriptome sequences of BTV-1 serotype-infected and mock-infected OLMECs and subsequently performed bioinformatics differential analysis. Our analysis revealed 1215 differentially expressed mRNA transcripts, 82 differentially expressed long noncoding RNAs (lncRNAs) transcripts, 63 differentially expressed microRNAs (miRNAs) transcripts, and 42 differentially expressed circular RNAs (circRNAs) transcripts. Annotation from Gene Ontology, enrichment from the Kyoto Encyclopedia of Genes and Genomes, and construction of endogenous competing RNA network analysis revealed that the differentially expressed RNAs primarily participated in viral sensing and signal transduction pathways, antiviral and immune responses, inflammation, and extracellular matrix (ECM)-related pathways. Furthermore, protein‒protein interaction network analysis revealed that BTV may regulate the conformation of ECM receptor proteins and change their biological activity through a series of complex mechanisms. Finally, on the basis of real-time fluorescence quantitative polymerase chain reaction results, the expression trends of the differentially expressed RNA were consistent with the whole-transcriptome sequencing data, such as downregulation of the expression of COL4A1, ITGA8, ITGB5, and TNC and upregulation of the expression of CXCL10, RNASEL, IRF3, IRF7, and IFIHI. This study provides a novel perspective for further investigations of the mechanism of the ECM in the BTV-host interactome and the pathogenesis of lung microvascular endothelial cells.

Advances in Juvenile Dermatomyositis: Pathophysiology, Diagnosis, Treatment and Interstitial Lung Diseases-A Narrative Review.

Juvenile idiopathic inflammatory myopathy (JIIM) is a rare systemic autoimmune disease characterized by skeletal muscle weakness with or without a skin rash. Juvenile dermatomyositis (JDM) is the most common subtype of JIIM, accounting for 80% of JIIM. Recent studies identified several myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs). Each MSA or MAA is associated with distinct clinical features and outcomes, although there are several differences in the prevalence of MSA/MAA and autoantibody-phenotype relationships between age and ethnic groups. Histopathological studies have revealed critical roles of type I interferons and vasculopathy in the development of JDM. Serological classification mostly corresponds to clinicopathological classification. Novel therapeutic agents, such as biologics and Janus kinase inhibitors (JAKi), have been developed; however, to date, there is a lack of high-level evidence. As advances in treatment have reduced the mortality rate of JIIM, recent studies have focused on medium- and long-term outcomes. However, rapidly progressive interstitial lung disease (RP-ILD) remains a major cause of death in anti-melanoma differentiation gene 5 autoantibody-positive JDM. Early diagnosis and intervention using a multi-drug regimen is critical for the treatment of RP-ILD. Rituximab and JAKi may reduce mortality in patients with JDM-associated RP-ILD refractory to conventional therapy.

African swine fever virus MGF360-4L protein attenuates type I interferon response by suppressing the phosphorylation of IRF3.

African swine fever (ASF) is a highly contagious and lethal disease of swine caused by African swine fever virus (ASFV), and the mortality rate caused by virulent stains can approach 100%. Many ASFV viral proteins suppress the interferon production to evade the host's innate immune responses. However, whether ASFV MGF360-4L could inhibit type I interferon (IFN-I) signaling pathway and the underlying molecular mechanisms remain unknown. Our study, indicated that ASFV MGF360-4L could negatively regulates the cGAS-STING mediated IFN-I signaling pathway. Overexpressing ASFV MGF360-4L could inhibit the cGAS/STING signaling pathway by inhibiting the interferon-ß promoter activity, which was induced by cGAS/STING, TBK1, and IRF3-5D, and further reduced the transcriptional levels of ISG15, ISG54, ISG56, STAT1, STAT2, and TYK2. Confocal microscopy and immunoprecipitation revealed that MGF360-4L co-localized and interacted with IRF3, and WB revealed that ASFV MGF360-4L suppressed the phosphorylation of IRF3. 4L-F2 (75-162 aa) and 4L-F3 (146-387 aa) were the crucial immunosuppressive domains and sites. Altogether, our study reveals ASFV MGF360-4L inhibited cGAS-STING mediated IFN-I signaling pathways, which provides insights into an evasion strategy of ASFV involving in host's innate immune responses.

Biologics in Systemic Lupus Erythematosus: Recent Evolutions and Benefits.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by significant autoantibodies, particularly targeting nuclear antigens. SLE pathogenesis involves genetic, environmental, and hormonal factors. The disease course includes flares and remission and involves various organs. Recent therapeutic progresses, including biologics, have improved management and prognosis, though the long-term impact of novel therapies remains to be determined. Biologics in SLE: Rituximab, the earliest B-cell-oriented biologic, binds CD20 and depletes CD20+ B cells, leading to remission in some SLE patients. Belimumab is a B-cell-activating factor (BAFF) inhibitor with a recent additional indication for lupus nephritis. The CALIBRATE and BLISS-BELIEVE studies investigated combinations of these drugs with conventional therapies, showing varied efficacy. Ocrelizumab and obinutuzumab, newer CD20-oriented SLE therapies, together with ofatumumab and veltuzumab, are also promising. The latest trials highlight their efficacy and safety. Anifrolumab, targeting type-I interferon receptors, was evaluated in the TULIP 1/2 trials. The ongoing TULIP LTE trial supports the long-term safety and efficacy of anifrolumab. Additionally, the IRIS Phase III trial is exploring anifrolumab for lupus nephritis, showing favorable renal responses. Tocilizumab and secukinumab are being assessed for SLE, with mixed outcomes. Several biologics targeting the C5 complement protein, together with immunomodulators and immunotherapeutics, are also under investigation for potential benefits in SLE. DISCUSSION: Biologics in SLE target specific immune components, aiming to improve disease control and reduce the side effects of conventional therapy. However, trial outcomes vary due to factors like inclusion criteria and trial design. CONCLUSIONS: Biotechnology progress enables targeted biologic therapies for SLE, reducing disease activity and improving patients' quality of life.

Mycobacterial peptidyl prolyl isomerase A activates STING-TBK1-IRF3 signaling to promote IFNß release in macrophages.

Peptidyl prolyl isomerases (PPIases) are well-conserved protein-folding enzymes that moonlight as regulators of bacterial virulence. Peptidyl prolyl isomerase A, PPiA (Rv0009) is a secretory protein of Mycobacterium tuberculosis that possesses sequence and structural similarity to eukaryotic cyclophilins. In this study, we validated the interaction of PPiA with stimulator of interferon genes (STING) using both, Escherichia coli-based and mammalian in vitro expression systems. In vitro pull-down assays confirmed that the cytosolic domain of STING interacts with PPiA, and moreover, we found that PPiA could induce dimerization of STING in macrophages. In silico docking analyses suggested that the PXXP (PDP) motif of PPiA is crucial for interaction with STING, and concordantly, mutations in the PDP domain (PPiA MUT-II) abrogated this interaction, as well as the ability of PPiA to facilitate STING dimerization. In agreement with these observations, fluorescence microscopy demonstrated that STING and wild-type PPiA, but not PPiA MUT-II, could colocalize when expressed in HEK293 cells. Highlighting the importance of the PDP domain further, PPiA, but not PPiA MUT-II could activate Tank binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) signaling to promote the release of interferon-beta (IFNß). PPiA, but not PPiA MUT-II expressed in Mycobacterium smegmatis induced IFNß release and facilitated bacterial survival in macrophages in a STING-dependent manner. The PPiA-induced release of IFNß was c-GAS independent. We conclude that PPiA is a previously undescribed mycobacterial regulator of STING-dependent type I interferon production from macrophages.

VHL synthetic lethality screens uncover CBF-ß as a negative regulator of STING.

Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of VHL, and uncover that loss of Core Binding Factor ß (CBF-ß) causes cell death in VHL-null ccRCC cell lines and impairs tumour establishment and growth in vivo. This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) in VHL-null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-ß. Mechanistically, CBF-ß loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-ß at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-ß in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.

N-myc and STAT interactor degrades interferon regulatory factor 7 mediated type I interferon signaling to promote duck Tembusu virus replication.

N-myc and STAT interactor (NMI) is an interferon-induced protein, which plays a variety of biological functions by participating in signal transduction and transcriptional activation, it has been reported to regulate antiviral response of different viruses in many species. However, the role of NMI in ducks during Duck Tembusu Virus (DTMUV) infection is completely unknown. In order to reveal whether duck NMI (duNMI) is involved in the antiviral response in the process of DTMUV infection and its role, we cloned and identified duNMI gene, and conducted sequence analysis of duNMI, the open reading frame region of duNMI gene is 1,137 bp, encoding 378 amino acid residues (aa), including 3 domains, Coiled-coil domain (22-126aa), NMI/IFP 35 domain 1 (NID1) domain (174-261aa) and NMI/IFP 35 domain 2 (NID2) domain (272-360aa). Analysis of tissue distribution of duNMI in 7-day-old ducks shows that the expression of duNMI is the highest in harderian gland, followed by small intestine and pancreas. Subsequently, we found that mRNA level of duNMI increases significantly after DTMUV stimulation, and overexpression of duNMI inhibits DTMUV replication in a dose-dependent manner. Besides, duNMI inhibits the transcriptional activity of IFN-I related cytokines. Specifically, we confirmed that duNMI interacts with duck regulatory factor 7 (duIRF7) through NID1 and NID2 domains and inhibit its expression and activated-IFN-ß. These results support that duNMI is an inhibitor of antiviral innate immune response in the process of DTMUV infection, which will provide a theoretical basis for the prevention of DTMUV infection.

Monogenic lupus - from gene to targeted therapy.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by loss of tolerance to nuclear antigens. The formation of autoantibodies and the deposition of immune complexes trigger inflammatory tissue damage that can affect any part of the body. In most cases, SLE is a complex disease involving multiple genetic and environmental factors. Despite advances in the treatment of SLE, there is currently no cure for SLE and patients are treated with immunosuppressive drugs with significant side effects. The elucidation of rare monogenic forms of SLE has provided invaluable insights into the molecular mechanisms underlying systemic autoimmunity. Harnessing this knowledge will facilitate the development of more refined and reliable biomarker profiles for diagnosis, therapeutic monitoring, and outcome prediction, and guide the development of novel targeted therapies not only for monogenic lupus, but also for complex SLE.

Immune response in diseased and healthy common carp exposed to carp edema virus.

The common carp is one of the most economically valuable freshwater fish worldwide and its aquaculture can be severely affected by the koi sleepy disease (KSD)/carp edema virus disease (CEVD). This study explores a natural outbreak of CEVD in a pond containing both clinically healthy and diseased fish of various origins exposed to the virus. We investigated mRNA expression of genes associated with known antiviral immune mechanisms, such as type I interferon signalling and cell-mediated cytotoxicity, and performed a comprehensive protein expression analysis to highlight differences between the two groups in various organs. Significant differences in expression profiles of common carp with and without clinical signs were found to be strongly dependent on the organ from which the sample originated. Components of the complement cascade, including various C3 proteins, exhibited upregulation only in less affected organs, specifically the head kidney and spleen. Other complement proteins such as B/C2 and C9 showed upregulation in the kidney, spleen, and gills but not in the skin. Conversely, lysozymes C and G, were observed to be upregulated in the most affected organs of the skin and gills. This study submits the first description of the immune system related proteome using a mass spectrometry on the samples isolated from fish infected with CEV. It also offers a unique comparison of immune reaction of CEV infected and healthy fish under an infectious pressure.

UDP-glucose ceramide glucosyltransferase specifically upregulated in plasmacytoid dendritic cells regulates type I interferon production upon CpG stimulation.

Plasmacytoid dendritic cells (pDCs) are a distinct subset of DCs involved in immune regulation and antiviral immune responses. Recent studies have elucidated the metabolic profile of pDCs and reported that perturbations in amino acid metabolism can modulate their immune functions. Glycolipid metabolism is suggested to be highly active in pDCs; however, its significance remains unclear. In this study, bulk RNA-sequencing analysis confirmed the known pDC-marker expressions, including interleukin (IL)-3R (CD123), BDCA-2 (CD303), BDCA-4 (CD304), and toll-like receptor 9, compared with that of myeloid DCs (mDCs). Among the differentially expressed genes, UDP-glucose-ceramide glucosyltransferase (UGCG) expression was significantly upregulated in pDCs than in mDCs. Moreover, pDC-specific UGCG expression was observed at both the mRNA and protein levels in pDCs and pDC-like cell lines, including CAL-1 and PMDC05 cell lines. Pharmacological or clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9-mediated genetic inhibition of UGCG did not affect the pDC phenotype as evidenced by the persistent expression of IL-3R and BDCA-2 in pDC-like cell lines. However, UGCG knockout resulted in reduced type I interferon production in pDCs upon CpG activation. In addition, UGCG-knockout pDC-like cell lines exhibited reduced transduction by vesicular stomatitis virus-G pseudo-typed lentiviral vectors, suggesting that low UGCG expression hinders infectivity. Collectively, our findings suggest that pDC-specific UGCG expression is critical for cytokine production and antiviral immune responses in pDCs.

A novel role of ETV6 as a pro-viral factor in host response by inhibiting TBK1 phosphorylation.

E26-transforming specific (ETS) variant 6 (ETV6) is a transcription factor regulating the expression of interferon stimulating genes (ISGs) and involved in the embryonic development and hematopoietic regulation, but the role of ETV6 in host response to virus infection is not clear. In this study, we show that ETV6 was upregulated in DF-1 cells with poly(I:C) stimulation or IBDV, AIV and ARV infection via engagement of dsRNA by MDA5. Overexpression of ETV6 in DF-1 cells markedly inhibited IBDV-induced type I interferon (IFN-I) and ISGs expressions. In contrast, knockdown, or knockout of ETV6 remarkably inhibited IBDV replication via promoting IFN-I response. Furthermore, our data show that ETV6 negatively regulated host antiviral response to IBDV infection by interaction with TANK binding kinase 1 (TBK1) and subsequently inhibited its phosphorylation. These results uncovered a novel role of ETV6 as a pro-viral factor in host response by inhibiting TBK1 phosphorylation, furthering our understandings of RNA virus immunosuppression and providing a valuable clue to the development of antiviral reagents for the control of avian RNA virus infection.