Reduced G protein signaling despite impaired internalization and ß-arrestin recruitment in patients carrying a CXCR4Leu317fsX3 mutation causing WHIM syndrome.

WHIM syndrome is an inherited immune disorder caused by an autosomal dominant heterozygous mutation in CXCR4. The disease is characterized by neutropenia/leukopenia (secondary to retention of mature neutrophils in bone marrow), recurrent bacterial infections, treatment-refractory warts, and hypogammaglobulinemia. All mutations reported in WHIM patients lead to the truncations in the C-terminal domain of CXCR4, R334X being the most frequent. This defect prevents receptor internalization and enhances both calcium mobilization and ERK phosphorylation, resulting in increased chemotaxis in response to the unique ligand CXCL12. Here, we describe 3 patients presenting neutropenia and myelokathexis, but normal lymphocyte count and immunoglobulin levels, carrying what we believe to be a novel Leu317fsX3 mutation in CXCR4, leading to a complete truncation of its intracellular tail. The analysis of the L317fsX3 mutation in cells derived from patients and in vitro cellular models reveals unique signaling features in comparison with R334X mutation. The L317fsX3 mutation impairs CXCR4 downregulation and ß-arrestin recruitment in response to CXCL12 and reduces other signaling events - including ERK1/2 phosphorylation, calcium mobilization, and chemotaxis - all processes that are typically enhanced in cells carrying the R334X mutation. Our findings suggest that, overall, the L317fsX3 mutation may be causative of a form of WHIM syndrome not associated with an augmented CXCR4 response to CXCL12.

GBP2 acts as a member of the interferon signalling pathway in lupus nephritis.

Lupus nephritis (LN) is a common and serious clinical manifestation of systemic lupus erythematosus. However, the pathogenesis of LN is not fully understood. The currently available treatments do not cure the disease and appear to have a variety of side effects in the long term. The purpose of this study was to search for key molecules involved in the LN immune response through bioinformatics techniques to provide a reference for LN-specific targeted therapy. The GSE112943 dataset was downloaded from the Gene Expression Omnibus database, and 20 of the samples were selected for analysis. In total, 2330 differentially expressed genes were screened. These genes were intersected with a list of immune genes obtained from the IMMPORT immune database to obtain 128 differentially expressed immune-related genes. Enrichment analysis showed that most of these genes were enriched in the interferon signalling pathway. Gene set enrichment analysis revealed that the sample was significantly enriched for expression of the interferon signalling pathway. Further analysis of the core gene cluster showed that nine genes, GBP2, VCAM1, ADAR, IFITM1, BST2, MX2, IRF5, OAS1 and TRIM22, were involved in the interferon signalling pathway. According to our analysis, the guanylate binding protein 2 (GBP2), interferon regulatory factor 5 and 2'-5'-oligoadenylate synthetase 1 (OAS1) genes are involved in three interferon signalling pathways. At present, we do not know whether GBP2 is associated with LN. Therefore, this study focused on the relationship between GBP2 and LN pathogenesis. We speculate that GBP2 may play a role in the pathogenesis of LN as a member of the interferon signalling pathway. Further immunohistochemical results showed that the expression of GBP2 was increased in the renal tissues of LN patients compared with the control group, confirming this conjecture. In conclusion, GBP2 is a member of the interferon signalling pathway that may have implications for the pathogenesis of LN and serves as a potential biomarker for LN.

Role of GBP1 in innate immunity and potential as a tuberculosis biomarker.

Tuberculosis (TB) is a global health problem of major concern. Identification of immune biomarkers may facilitate the early diagnosis and targeted treatment of TB. We used public RNA-sequencing datasets of patients with TB and healthy controls to identify differentially expressed genes and their associated functional networks. GBP1 expression was consistently significantly upregulated in TB, and 4492 differentially expressed genes were simultaneously associated with TB and high GBP1 expression. Weighted gene correlation analysis identified 12 functional modules. Modules positively correlated with TB and high GBP1 expression were associated with the innate immune response, neutrophil activation, neutrophil-mediated immunity, and NOD receptor signaling pathway. Eleven hub genes (GBP1, HLA-B, ELF4, HLA-E, IFITM2, TNFRSF14, CD274, AIM2, CFB, RHOG, and HORMAD1) were identified. The least absolute shrinkage and selection operator model based on hub genes accurately predicted the occurrence of TB (area under the receiver operating characteristic curve = 0.97). The GBP1-module-pathway network based on the STRING database showed that GBP1 expression correlated with the expression of interferon-stimulated genes (GBP5, BATF2, EPSTI1, RSAD2, IFI44L, IFIT3, and OAS3). Our study suggests GBP1 as an optimal diagnostic biomarker for TB, further indicating an association of the AIM2 inflammasome signaling pathway in TB pathology.

Tupaia GBP1 Interacts with STING to Initiate Autophagy and Restrict Herpes Simplex Virus Type 1 Infection.

Stimulator of IFN genes (STING) is a key molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase to activate IFN expression and autophagy in the fight against microbial infection. The regulation of STING in the activation of IFN expression has been extensively reported, whereas the regulation of STING in the initiation of autophagy is still insufficiently determined. IFN-inducible guanylate-binding proteins (GBPs) are central to the cell-autonomous immunity in defending a host against viral, bacterial, and protozoan infections. In this study using the Chinese tree shrew (Tupaia belangeri chinensis), which is genetically close to primates, we found that Tupaia GBP1 (tGBP1) combines with Tupaia STING (tSTING), promotes autophagy, and moderately inhibits HSV type 1 (HSV-1) infection. The antiviral effects of tGBP1 are IFN independent. Mechanistically, tGBP1 interacted with tSTING, Tupaia sequestosome 1, and Tupaia microtubule associated protein 1 L chain 3, forming a complex which promotes autophagy in response to HSV-1 infection. This function of tGBP1 against HSV-1 infection was lost in tSTING knockout cells. Overexpression of either tSTING or its mutant tSTING-ΔCTT that can only activate autophagy rescued the anti-HSV-1 activity of tGBP1 in tSTING knockout cells. Our study not only elucidated the underlying mechanism of tGBP1 antiviral activity against HSV-1 infection, but also uncovered the regulation of tSTING in the initiation of autophagy in response to HSV-1 infection.

Redox-sensitive CDC-42 clustering promotes wound closure in C. elegans.

Tissue damage induces immediate-early signals, activating Rho small GTPases to trigger actin polymerization essential for later wound repair. However, how tissue damage is sensed to activate Rho small GTPases locally remains elusive. Here, we found that wounding the C. elegans epidermis induces rapid relocalization of CDC-42 into plasma membrane-associated clusters, which subsequently recruits WASP/WSP-1 to trigger actin polymerization to close the wound. In addition, wounding induces a local transient increase and subsequent reduction of H2O2, which negatively regulates the clustering of CDC-42 and wound closure. CDC-42 CAAX motif-mediated prenylation and polybasic region-mediated cation-phospholipid interaction are both required for its clustering. Cysteine residues participate in intermolecular disulfide bonds to reduce membrane association and are required for negative regulation of CDC-42 clustering by H2O2. Collectively, our findings suggest that H2O2-regulated fine-tuning of CDC-42 localization can create a distinct biomolecular cluster that facilitates rapid epithelial wound repair after injury.

Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis.

Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme catalyzing the crosslinking between Gln and Lys residues and involved in various pathophysiological events. Besides this crosslinking activity, TG2 functions as a deamidase, GTPase, isopeptidase, adapter/scaffold, protein disulfide isomerase, and kinase. It also plays a role in the regulation of hypusination and serotonylation. Through these activities, TG2 is involved in cell growth, differentiation, cell death, inflammation, tissue repair, and fibrosis. Depending on the cell type and stimulus, TG2 changes its subcellular localization and biological activity, leading to cell death or survival. In normal unstressed cells, intracellular TG2 exhibits a GTP-bound closed conformation, exerting prosurvival functions. However, upon cell stimulation with Ca2+ or other factors, TG2 adopts a Ca2+-bound open conformation, demonstrating a transamidase activity involved in cell death or survival. These functional discrepancies of TG2 open form might be caused by its multifunctional nature, the existence of splicing variants, the cell type and stimulus, and the genetic backgrounds and variations of the mouse models used. TG2 is also involved in the phagocytosis of dead cells by macrophages and in fibrosis during tissue repair. Here, we summarize and discuss the multifunctional and controversial roles of TG2, focusing on cell death/survival and fibrosis.

An initial assessment of the involvement of transglutaminase2 in eosinophilic bronchitis using a disease model developed in C57BL/6 mice.

The detailed pathogenesis of eosinophilic bronchitis (EB) remains unclear. Transglutaminase 2 (TG2) has been implicated in many respiratory diseases including asthma. Herein, we aim to assess preliminarily the relationship of TG2 with EB in the context of the development of an appropriate EB model through ovalbumin (OVA) sensitization and challenge in the C57BL/6 mouse strain. Our data lead us to propose a 50 µg dose of OVA challenge as appropriate to establish an EB model in C57BL/6 mice, whereas a challenge with a 400 µg dose of OVA significantly induced asthma. Compared to controls, TG2 is up-regulated in the airway epithelium of EB mice and EB patients. When TG2 activity was inhibited by cystamine treatment, there were no effects on airway responsiveness; in contrast, the lung pathology score and eosinophil counts in bronchoalveolar lavage fluid were significantly increased whereas the cough frequency was significantly decreased. The expression levels of interleukin (IL)-4, IL-13, IL-6, mast cell protease7 and the transient receptor potential (TRP) ankyrin 1 (TRPA1), TRP vanilloid 1 (TRPV1) were significantly decreased. These data open the possibility of an involvement of TG2 in mediating the increased cough frequency in EB through the regulation of TRPA1 and TRPV1 expression. The establishment of an EB model in C57BL/6 mice opens the way for a genetic investigation of the involvement of TG2 and other molecules in this disease using KO mice, which are often generated in the C57BL/6 genetic background.

Interplay Between Gluten, HLA, Innate and Adaptive Immunity Orchestrates the Development of Coeliac Disease.

Several environmental, genetic, and immune factors create a "perfect storm" for the development of coeliac disease: the antigen gluten, the strong association of coeliac disease with HLA, the deamidation of gluten peptides by the enzyme transglutaminase 2 (TG2) generating peptides that bind strongly to the predisposing HLA-DQ2 or HLA-DQ8 molecules, and the ensuing unrestrained T cell response. T cell immunity is at the center of the disease contributing to the inflammatory process through the loss of tolerance to gluten and the differentiation of HLA-DQ2 or HLA-DQ8-restricted anti-gluten inflammatory CD4+ T cells secreting pro-inflammatory cytokines and to the killing of intestinal epithelial cells by cytotoxic intraepithelial CD8+ lymphocytes. However, recent studies emphasize that the individual contribution of each of these cell subsets is not sufficient and that interactions between these different populations of T cells and the simultaneous activation of innate and adaptive immune pathways in distinct gut compartments are required to promote disease immunopathology. In this review, we will discuss how tissue destruction in the context of coeliac disease results from the complex interactions between gluten, HLA molecules, TG2, and multiple innate and adaptive immune components.

Celiac Disease-Type Tissue Transglutaminase Autoantibody Deposits in Kidney Biopsies of Patients with IgA Nephropathy.

An association between celiac disease and IgA nephropathy (IgAN) has been suggested. In celiac disease, in addition to circulating in serum, IgA-class tissue transglutaminase (tTG) autoantibodies are deposited in the small bowel mucosa and extraintestinal organs. In this case series of IgAN patients with or without celiac disease, we studied whether celiac disease-type IgA-tTG deposits occur in kidney biopsies. The study included nine IgAN patients, four of them with celiac disease. At the time of the diagnostic kidney biopsy serum tTG autoantibodies were measured and colocalization of IgA and tTG was investigated in the frozen kidney biopsies. Three IgAN patients with celiac disease had IgA-tTG deposits in the kidney even though in two of these the celiac disease diagnosis had been set years later. These deposits were not found in a patient with already diagnosed celiac disease following a gluten-free diet. Of the five non-celiac IgAN patients, three had IgA-tTG deposits in the kidney. We conclude that tTG-targeted IgA deposits can be found in the kidney biopsies of gluten-consuming IgAN patients but their specificity to celiac disease seems limited.

Transglutaminase 2 Regulates Innate Immunity by Modulating the STING/TBK1/IRF3 Axis.

We have recently shown that type 2 transglutaminase (TG2) plays a key role in the host's inflammatory response during bacterial infections. In this study, we investigated whether the enzyme is involved in the regulation of the STING pathway, which is the main signaling activated in the presence of both self- and pathogen DNA in the cytoplasm, leading to type I IFN (IFN I) production. In this study, we demonstrated that TG2 negatively regulates STING signaling by impairing IRF3 phosphorylation in bone marrow-derived macrophages, isolated from wild-type and TG2 knockout mice. In the absence of TG2, we found an increase in the IFN-ß production and in the downstream JAK/STAT pathway activation. Interestingly, proteomic analysis revealed that TG2 interacts with TBK1, affecting its interactome composition. Indeed, TG2 ablation facilitates the TBK1-IRF3 interaction, thus indicating that the enzyme plays a negative regulatory effect on IRF3 recruitment in the STING/TBK1 complex. In keeping with these findings, we observed an increase in the IFNß production in bronchoalveolar lavage fluids from COVID-19-positive dead patients paralleled by a dramatic decrease of the TG2 expression in the lung pneumocytes. Taken together, these results suggest that TG2 plays a negative regulation on the IFN-ß production associated with the innate immunity response to the cytosolic presence of both self- and pathogen DNA.

T Cell Response Toward Tissue-and Epidermal-Transglutaminases in Coeliac Disease Patients Developing Dermatitis Herpetiformis.

The reason why only few coeliac patients develop the cutaneous manifestation of the disease, named dermatitis herpetiformis (DH), is still unknown. Epidermal transglutaminase (TG3) has been described as the main autoantigen of humoral immunity in DH but the mechanisms leading to this autoimmune response remain obscure. Here we characterized T cells from skin, gut and peripheral blood of DH and coeliac disease (CD) patients, evaluated the impact of the gluten-free diet on circulating T lymphocytes' phenotype and investigated antigen specific T cell response toward epidermal and tissue transglutaminase (TG2). DH patients showed an increased frequency of skin-derived T cells producing TNFα when compared to CD patients. Moreover, circulating T cells producing TNFα and IL-17A positively correlated with clinical score of skin disease activity and decreased after gluten-free diet. Finally, TG2 and TG3-specific T cells resulted more reactive to antigens stimulation in DH patients and showed cross reactivity toward the two autoantigens in both the group of patients. Our data suggest a role of TNFα and IL-17A producing cells in the development of DH and, for the first time, show the existence of a crossed T cell response toward the two transglutaminases isoforms, thus suggesting new insights on T cells role in skin damage.

Liver involvement in patients with coeliac disease: proof of causality using IgA/anti-TG2 colocalisation techniques.

AIMS: Despite clinical evidence of liver involvement in patients with coeliac disease (CeD), there is a lack of a method to prove this association. METHODS: Of 146 treatment-naive patients with CeD, 26 had liver dysfunction. Liver biopsies and corresponding small intestinal biopsies were obtained from these 26 patients. Multicolour immunohistochemical and immunofluorescence confocal microscopic studies were performed on paraffin-embedded tissue to detect the IgA/anti-TG2 deposits. Follow-up liver biopsies were taken after a gluten-free diet. RESULTS: Twenty-six out of the 146 patients (17.8%) with suspected coeliac-associated liver disease on histological examination revealed irregular sinusoidal dilatation in 15 (57.6%), steatohepatitis in 4 (15.3%), non-specific chronic hepatitis in 3 (11.5%), autoimmune hepatitis in 2 (7.6%) biopsies, including cirrhosis in one of them, irregular perisinusoidal fibrosis and changes of non-cirrhotic portal fibrosis in one biopsy each (3.8%). IgA/anti-tTG deposits were observed in 22 (84.6%) liver biopsies by dual immunohistochemistry technique, and in 24 (92.3%) by confocal immunofluorescence technique and in all corresponding duodenal biopsies (100%). Overall, IgA/anti-tTG deposits showed 100% sensitivity, 77% specificity and 85% positive predictive value for establishing an association of extraintestinal pathology and CeD using archived tissues. Follow-up liver biopsies could be obtained in five patients; four of them showed not only resolution of the histological lesions but disappearance of IgA/anti-tTG co-localisation. CONCLUSIONS: Data of the present study adds to the body of evidence that liver lesions in patients with CeD are disease related and may have been caused by a similar pathogenic mechanism that causes intestinal changes.

Accuracy of Screening Tests for Celiac Disease in Asymptomatic Patients With Type 1 Diabetes.

INTRODUCTION: To evaluate the diagnostic performance of celiac serologic tests in asymptomatic patients with type 1 diabetes (T1D). METHODS: Patients with T1D asymptomatic for celiac disease were prospectively screened with immunoglobulin A anti-tissue transglutaminase. Test characteristics were calculated and optimal cutoffs for a positive screen determined. RESULTS: Two thousand three hundred fifty-three patients were screened and 101 proceeded to biopsy. The positive predictive value of immunoglobulin A anti-tissue transglutaminase at the assay referenced upper limit of normal (30CU) was 85.9%, and the sensitivity and specificity were 100% and 38%, respectively. DISCUSSION: Thresholds extrapolated from the general population for the diagnostic evaluation of celiac disease are not suitable for use in asymptomatic T1D patients. Population-specific screening cutoffs are required.

The GBP1 microcapsule interferes with IcsA-dependent septin cage assembly around Shigella flexneri.

Many cytosolic bacterial pathogens hijack the host actin polymerization machinery to form actin tails that promote direct cell-to-cell spread, enabling these pathogens to avoid extracellular immune defenses. However, these pathogens are still susceptible to intracellular cell-autonomous immune responses that restrict bacterial actin-based motility. Two classes of cytosolic antimotility factors, septins and guanylate-binding proteins (GBPs), have recently been established to block actin tail formation by the human-adapted bacterial pathogen Shigella flexneri. Both septin cages and GBP1 microcapsules restrict S. flexneri cell-to-cell spread by blocking S. flexneri actin-based motility. While septins assemble into cage-like structures around immobile S. flexneri, GBP1 forms microcapsules around both motile and immobile bacteria. The interplay between these two defense programs remains elusive. Here, we demonstrate that GBP1 microcapsules block septin cage assembly, likely by interfering with the function of S. flexneri IcsA, the outer membrane protein that promotes actin-based motility, as this protein is required for septin cage formation. However, S. flexneri that escape from GBP1 microcapsules via the activity of IpaH9.8, a type III secreted effector that promotes the degradation of GBPs, are often captured within septin cages. Thus, our studies reveal how septin cages and GBP1 microcapsules represent complementary host cell antimotility strategies.

Interferon-γ activated T-cell IRGM-autophagy axis in oral lichen planus.

Oral lichen planus (OLP) is an inflammatory immune disease featured by dense T-cell infiltrate and basal keratinocytes degeneration. Immunity related GTPase M (IRGM) is vital for the induction of autophagy. Our previous studies have demonstrated aberrant autophagy in OLP, however, the involvement of IRGM-autophagy axis in OLP has not yet been revealed. The expression of IRGM and autophagy activity were evaluated in oral mucosal tissues and peripheral T cells of OLP patients and healthy controls, respectively. We found significant upregulation of IRGM and LC3B in lesions of patients with OLP as compared with healthy donors. IRGM, LC3B and NOD2 levels were also elevated in the peripheral T cells of OLP. Then, knockdown of IRGM after electrotransfection with siRNA resulted in attenuated autophagy, growth inhibition, and apoptosis of T cells. In addition, preincubation with IFN-γ promoted the expression of IRGM mRNA and induced autophagy in T cells. Furthermore, IFN-γ decreased the proliferation and apoptosis of T cells, whereas facilitated the viability of keratinocytes in a co-culture system of activated T cells and keratinocytes. Taken together, activated IRGM-autophagy axis under IFN-γ regulation in T cells might participate in the immunoregulatory mechanism of OLP.

Is Endoscopic Assessment of the Esophagus and Stomach Enough to Determine the Need for Biopsy at These Sites in Pediatric Patients Undergoing Endoscopy for Elevated TTG?

OBJECTIVES: The goal of our study was to determine whether visual assessment of the esophagus and stomach could predict abnormal histology and determine the frequency of interventions based on biopsies in patients undergoing endoscopy for elevated tissue transglutaminase immunoglobulin A antibody (TTG). METHODS: Pathology records were searched for patients with biopsy performed for elevated TTG. Pathology report, endoscopy report, and follow-up were obtained and slides from the duodenum reviewed. Pathology was considered gold standard for sensitivity and specificity calculations. RESULTS: 240 patients were included. 215 patients had esophageal biopsies performed. Esophageal endoscopic visual assessment had sensitivity of 47% and specificity of 93% for abnormal histology. 16(7%) patients had therapy or referral related to results and, of these, 6(38%) had visually normal endoscopy. 237 biopsies were performed of stomach. Gastric endoscopic visual assessment had a sensitivity and specificity of 20% and 87%. 24(10%) patients had therapy based on findings and, of these, 12 (50%) had visually normal endoscopy. CONCLUSIONS: Endoscopic assessment of esophagus and stomach has low sensitivity and high specificity for pathologic abnormalities when indication for endoscopy is elevated TTG. When endoscopy is visually normal clinical interventions based on biopsy are rare, and foregoing biopsy may be considered.

The mitochondrial protein ERAL1 suppresses RNA virus infection by facilitating RIG-I-like receptor signaling.

Mitochondria not only serve as a platform for innate immune signaling transduction but also enhance immune responses by releasing mitochondrial DNA and RNA into the cytoplasm. However, whether mitochondrial matrix proteins could be liberated and involved in immune responses remains enigmatic. Here, we identify the mitochondrial protein ERA G-protein-like 1 (ERAL1) as a mitochondrial antiviral signaling protein (MAVS)-interacting protein by using proximity-based labeling technology. ERAL1 deficiency markedly reduces the downstream antiviral signaling triggered by RNA viruses. Moreover, ERAL1-deficient mice are more susceptible to lethality following RNA virus infection than wild-type mice. After virus infection, ERAL1 is released from mitochondria through the BAX/BAK pore. The cytosolic ERAL1 facilitates lysine 63 (K63)-linked ubiquitination of retinoicacid inducible gene-1 (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) and promotes downstream MAVS polymerization, thus positively regulating antiviral responses.

Genetic bioengineering of overexpressed guanylate binding protein family BmAtlastin-n enhances silkworm resistance to Nosema bombycis.

Microsporidia are obligate single-celled eukaryote parasites. Microsporidian infection can cause large economic losses to beneficial insects such as silkworms and honey bees. Identification of resistance biomacromolecules and breeding of transgenic lines resistant to the microsporidian Nosema bombycis are important for disease management. We previously used transcriptome analysis to identify a guanylate binding protein family BmAtlastin-n gene that was significantly upregulated after Nosema bombycis infection, and we determined that the molecule was highly expressed in resistance-related tissues such as the midgut, fat body and the epidermis. The transgenic silkworm line overexpressing BmAtlastin-n biomolecules had economic characters similar to those of non-transgenic lines. The transgenic OE-BmAtlastin-n lines had significantly improved survival after microspore infection. We used RT-PCR and H&E staining to show that the number of spores in the transgenic lines was significantly lower than in the control lines. In this study, we identified a BmAtlastin-n macromolecule with resistance to N. bombycis and developed a transgenic line. The results improved understanding of the GBP protein family and provided biomacromolecule material for the treatment and prevention of microsporidia.

Inducible Guanylate-Binding Protein 7 Facilitates Influenza A Virus Replication by Suppressing Innate Immunity via NF-κB and JAK-STAT Signaling Pathways.

Guanylate-binding protein 7 (GBP7) belongs to the GBP family, which plays key roles in mediating innate immune responses to intracellular pathogens. Thus far, GBP7 has been reported to be a critical cellular factor against bacterial infection. However, the relationship between GBP7 and influenza A virus (IAV) replication is unknown. Here, we showed that GBP7 expression was significantly upregulated in the lungs of mice, human peripheral blood mononuclear cells (PBMCs), and A549 cells during IAV infection. Using the CRISPR-Cas9 system and overexpression approaches, it was found that GBP7 knockout inhibited IAV replication by enhancing the expression of IAV-induced type I interferon (IFN), type III IFN, and proinflammatory cytokines. Conversely, overexpression of GBP7 facilitated IAV replication by suppressing the expression of those factors. Furthermore, GBP7 knockout enhanced IAV-induced nuclear factor-κB (NF-κB) activation and phosphorylation of stat1 and stat2; overexpression of GBP7 had the opposite effect. Our data indicated that GBP7 suppresses innate immune responses to IAV infection via NF-κB and JAK-STAT signaling pathways. Taken together, upon IAV infection, the induced GBP7 facilitated IAV replication by suppressing innate immune responses to IAV infection, which suggested that GBP7 serves as a therapeutic target for controlling IAV infection.IMPORTANCE So far, few studies have mentioned the distinct function of guanylate-binding protein 7 (GBP7) on virus infection. Here, we reported that GBP7 expression was significantly upregulated in the lungs of mice, human PBMCs, and A549 cells during IAV infection. GBP7 facilitated IAV replication by suppressing the expression of type I interferon (IFN), type III IFN, and proinflammatory cytokines. Furthermore, it was indicated that GBP7 suppresses innate immune responses to IAV infection via NF-κB and JAK-STAT signaling pathways. Taken together, our results elucidate a critical role of GBP7 in the host immune system during IAV infection.

Villous atrophy persistence in celiac disease despite following a gluten-free diet must be clarified

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