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Frontiers in Immunology 2023Type I interferonopathies are a heterogenic group of rare diseases associated with an increase in type I interferon (IFN). The main challenge for the study of Type I...
Type I interferonopathies are a heterogenic group of rare diseases associated with an increase in type I interferon (IFN). The main challenge for the study of Type I interferonopathies is the lack of a well-founded animal model to better characterize the phenotype as well as to perform fast and large drug screenings to offer the best treatment options. In this study, we report the development of a transgenic zebrafish model of Type I interferonopathy overexpressing carrying the mutation p.Arg742His (), corresponding to the human mutation p.Arg779His. RNA sequence analysis from larvae revealed a systemic inflammation and IFN signature upon a suboptimal poly I:C induction compared with wild-type larvae, confirming the phenotype observed in patients suffering from Type I interferonopathies. More interestingly, the phenotype was manifested in the zebrafish inflammation and Type I IFN reporters and , respectively, making this zebrafish model suitable for future high-throughput chemical screening (HTS). Using the unique advantages of the zebrafish model for gene editing, we have generated knocked down for and , which completely abrogated the Poly I:C induction and activation of the GFP of the reporters. Finally, we used an FDA-approved drug, Baricitinib (Jak1/Jak2 inhibitor), which was able to reduce the inflammation and the ISG expression. Our results demonstrate the potential of this model to further understand AGS pathological mechanisms and to identify novel therapeutic drugs by HTS.
Topics: Animals; Humans; Inflammation; Interferon Type I; Poly I; Zebrafish; Interferon-Induced Helicase, IFIH1
PubMed: 38077314
DOI: 10.3389/fimmu.2023.1294766 -
International Journal of Molecular... Nov 2023CRL1505 beneficially modulates the inflammation-coagulation response during respiratory viral infections. This study evaluated the capacity of the peptidoglycan...
CRL1505 beneficially modulates the inflammation-coagulation response during respiratory viral infections. This study evaluated the capacity of the peptidoglycan obtained from the CRL1505 strain (PG-Lr1505) to modulate the immuno-coagulative response triggered by the viral pathogen-associated molecular pattern poly(I:C) in the respiratory tract. Adult BALB/c mice were nasally treated with PG-Lr1505 for two days. Treated and untreated control mice were then nasally challenged with poly(I:C). Mice received three doses of poly(I:C) with a 24 h rest period between each administration. The immuno-coagulative response was studied after the last administration of poly(I:C). The challenge with poly(I:C) significantly increased blood and respiratory pro-inflammatory mediators, decreased prothrombin activity (PT), and increased von Willebrand factor (vWF) levels in plasma. Furthermore, tissue factor (TF), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) expressions were increased in the lungs. PG-Lr1505-treated mice showed significant modulation of hemostatic parameters in plasma (PT in %, Control = 71.3 ± 3.8, PG-Lr1505 = 94.0 ± 4.0, < 0.01) and lungs. Moreover, PG-Lr1505-treated mice demonstrated reduced TF in F4/80 cells from lungs, higher pro-inflammatory mediators, and increased IL-10 compared to poly(I:C) control mice (IL-10 in pg/mL, Control = 379.1 ± 12.1, PG-Lr1505 = 483.9 ± 11.3, < 0.0001). These changes induced by PG-Lr1505 correlated with a significant reduction in lung tissue damage. Complementary in vitro studies using Raw 264.7 cells confirmed the beneficial effect of PG-Lr1505 on poly(I:C)-induced inflammation, since increased IL-10 expression, as well as reduced damage, production of inflammatory mediators, and hemostatic parameter expressions were observed. In addition, protease-activated receptor-1 (PAR1) activation in lungs and Raw 264.7 cells was observed after TLR3 stimulation, which was differentially modulated by PG-Lr1505. The peptidoglycan from CRL1505 is able to regulate inflammation, the procoagulant state, and PAR1 activation in mice and macrophages in the context of the activation of TLR3 signaling pathways, contributing to a beneficial modulation of inflammation-hemostasis crosstalk.
Topics: Animals; Mice; Interleukin-10; Lacticaseibacillus rhamnosus; Peptidoglycan; Cytokines; Receptor, PAR-1; Toll-Like Receptor 3; Lung; Inflammation; Hemostatics; Inflammation Mediators
PubMed: 38069229
DOI: 10.3390/ijms242316907 -
Brain, Behavior, and Immunity Jan 2024To clarify the role of gut mucosal immunity in ASD, we evaluated, in the early-life immune activation (EIA) mouse model, the effects of administration of a monoclonal...
To clarify the role of gut mucosal immunity in ASD, we evaluated, in the early-life immune activation (EIA) mouse model, the effects of administration of a monoclonal antibody directed against the integrin alpha4 beta7 (α4β7 mAb), blocking the leukocyte homing into the gut mucosa. EIA is a double-hit variant of the maternal immune-activation (MIA) model, including both prenatal (Poly I:C) and postnatal (LPS) immune challenges. In C57BL6/J EIA male adult offspring mice, IL-1β and IL-17A mRNA colonic tissue content increased when compared with controls. Cytofluorimetric analyses of lymphocytes isolated from mesenteric lymph-nodes (MLN) and spleens of EIA mice show increased percentage of total and CD4α4β7, unstimulated and stimulated IL-17A and stimulated IFN-γ lymphocytes in MLN and CD4α4β7 unstimulated and stimulated IL-17A and stimulated IFN-γ lymphocytes in the spleen. Treatment with anti-α4β7 mAb in EIA male mice was associated with colonic tissue IL-1β, and IL-17A mRNA content and percentage of CD4 IL-17A and IFN-γ lymphocytes in MLN and spleens comparable to control mice. The anti-α4β7 mAb treatment rescue social novelty deficit showed in the three-chamber test by EIA male mice. Increased levels of IL-6 and IL-1β and decreased CD68 and TGF-β mRNAs were also observed in hippocampus and prefrontal cortex of EIA male mice together with a reduction of BDNF mRNA levels in all brain regions examined. Anti-α4β7 mAb treatment restored the expression of BDNF, TGF-β and CD68 in hippocampus and prefrontal cortex. Improvement of the gut inflammatory status, obtained by a pharmacological agent acting exclusively at gut level, ameliorates some ASD behavioral features and the neuroinflammatory status. Data provide the first preclinical indication for a therapeutic strategy against gut-immune activation in ASD subjects with peripheral increase of gut-derived (α4β7+) lymphocytes expressing IL-17A.
Topics: Humans; Adult; Pregnancy; Female; Male; Mice; Animals; Interleukin-17; Autism Spectrum Disorder; Brain-Derived Neurotrophic Factor; Integrins; Antibodies, Monoclonal; Transforming Growth Factor beta; RNA, Messenger
PubMed: 37793488
DOI: 10.1016/j.bbi.2023.09.024 -
Frontiers in Immunology 2023The cultured can meet the market demand in the context of the decline of wild resources, but the disease in the high-density culture process also deserves attention....
INTRODUCTION
The cultured can meet the market demand in the context of the decline of wild resources, but the disease in the high-density culture process also deserves attention. Therefore, understanding the immune regulation mechanisms of will be the basis for obtaining high benefits in artificial culture.
METHODS
To explore the viral response mechanism of , RNA-seq was applied to identify the transcriptomic changes of the liver and spleen in by poly (I:C) stress.
RESULTS
The DEGs (liver: 2186 to 3123; spleen 1542 to 2622) and up-regulated genes (liver: 1231 to 1776; spleen 769 to 1502) in the liver and spleen increased with the prolongation (12h to 48h) of poly (I:C)-stimulation time. This means needs to mobilize more functional genes in response to longer periods of poly (I:C)-stimulation. Despite the responses of to poly (I:C) showed tissue-specificity, we hypothesized that both liver and spleen of can respond to poly (I:C) challenge may be through promoting apoptosis of DNA-damaged cells, increasing the activity of immune-enhancing enzymes, and increasing energy supply based on DEGs annotation information.
CONCLUSIONS
Our results demonstrate the transcriptional responses of to poly (I:C)-stimulation, and these data provide the first resource on the genetic regulation mechanisms of against viruses. Furthermore, the present study can provide basic information for the prevention of viral diseases in artificial culture process.
Topics: Spleen; Poly I-C; Liver; Apoptosis; DNA Damage
PubMed: 37901224
DOI: 10.3389/fimmu.2023.1272393 -
Microbiology Spectrum Sep 2023The flavivirus non-structural protein 1 (NS1) is secreted from infected cells into the circulation and the serum levels correlate with disease severity. The effect of...
The flavivirus non-structural protein 1 (NS1) is secreted from infected cells into the circulation and the serum levels correlate with disease severity. The effect of secreted NS1 (sNS1) on non-infected mammalian immune cells is largely unknown. Here, we expressed recombinant sNS1 proteins of tick-borne encephalitis virus (TBEV) and West Nile virus (WNV) and investigated their effects on dendritic cell (DC) effector functions. Murine bone marrow-derived DCs (BMDCs) showed reduced surface expression of co-stimulatory molecules and decreased release of pro-inflammatory cytokines when treated with sNS1 of TBEV or WNV prior to poly(I:C) stimulation. Transcriptional profiles of BMDCs that were sNS1-exposed prior to poly(I:C) stimulation showed two gene clusters that were downregulated by TBEV or WNV sNS1 and that were associated with innate and adaptive immune responses. Functionally, both sNS1 proteins modulated the capacity for BMDCs to induce specific T-cell responses as indicated by reduced IFN-γ levels in both CD4 and CD8 T cells after BMDC co-cultivation. In human monocyte-derived DCs, poly(I:C)-induced upregulation of co-stimulatory molecules and cytokine responses were even more strongly impaired by TBEV sNS1 or WNV sNS1 pretreatment than in the murine system. Our findings indicate that exogenous flaviviral sNS1 proteins interfere with DC-mediated stimulation of T cells, which is crucial for the initiation of cell-mediated adaptive immune responses in human flavivirus infections. Collectively, our data determine soluble flaviviral NS1 as a virulence factor responsible for a dampened immune response to flavivirus infections. IMPORTANCE The effective initiation of protective host immune responses controls the outcome of infection, and dysfunctional T-cell responses have previously been associated with symptomatic human flavivirus infections. We demonstrate that secreted flavivirus NS1 proteins modulate innate immune responses of uninfected bystander cells. In particular, sNS1 markedly reduced the capacity of dendritic cells to stimulate T-cell responses upon activation. Hence, by modulating cellular host responses that are required for effective antigen presentation and initiation of adaptive immunity, sNS1 proteins may contribute to severe outcomes of flavivirus disease.
PubMed: 37707204
DOI: 10.1128/spectrum.02192-23 -
Frontiers in Immunology 2024Malaria remains a global health challenge, necessitating the development of effective vaccines. The RTS,S vaccination prevents (Pf) malaria but is ineffective against...
Malaria remains a global health challenge, necessitating the development of effective vaccines. The RTS,S vaccination prevents (Pf) malaria but is ineffective against (Pv) disease. Herein, we evaluated the murine immunogenicity of a recombinant PvCSP incorporating prevalent polymorphisms, adjuvanted with Alhydrogel or Poly I:C. Both formulations induced prolonged IgG responses, with IgG1 dominance by the Alhydrogel group and high titers of all IgG isotypes by the Poly I:C counterpart. Poly I:C-adjuvanted vaccination increased splenic plasma cells, terminally-differentiated memory cells (MBCs), and precursors relative to the Alhydrogel-combined immunization. Splenic B-cells from Poly I:C-vaccinated mice revealed an antibody-secreting cell- and MBC-differentiating gene expression profile. Biological processes such as antibody folding and secretion were highlighted by the Poly I:C-adjuvanted vaccination. These findings underscore the potential of Poly I:C to strengthen immune responses against Pv malaria.
Topics: Animals; Malaria Vaccines; Protozoan Proteins; Mice; Plasmodium vivax; Antibodies, Protozoan; Poly I-C; Malaria, Vivax; Aluminum Hydroxide; Immunoglobulin G; Female; Adjuvants, Immunologic; Immunity, Humoral; Immunity, Cellular; Mice, Inbred BALB C
PubMed: 38650939
DOI: 10.3389/fimmu.2024.1331474 -
Frontiers in Cellular and Infection... 2023The Janus kinase/signal transducers and activators of transcription (JAK-STAT) system regulates several biological processes by affecting transcription of genes as a...
BACKGROUND
The Janus kinase/signal transducers and activators of transcription (JAK-STAT) system regulates several biological processes by affecting transcription of genes as a response to cytokines and growth factors. In the present study, we have characterized the STAT genes in lumpfish ( L.), belonging to the order Perciformes, and investigated regulation of the JAK-STAT signaling pathway upon exposure to bacteria () and poly(I:C), the latter mimicking antiviral responses.
METHODS
Characterization and evolutionary analyses of the STATs were performed by phylogeny, protein domain, homology similarity and synteny analyses. Antibacterial and antiviral responses were investigated by performing KEGG pathway analysis.
RESULTS
We observed that lumpfish have , , , , , , and . Transcriptome-wide analyses showed that most components of the JAK-STAT pathway were present in lumpfish. -6, -10, -21, and were upregulated 6 hours post exposure (hpe) against bacteria while type I interferons (IFNs), , , , and were upregulated 24 hpe against poly(I:C).
CONCLUSIONS
Our findings shed light on the diversity and evolution of the STATs and the data show that the STAT genes are highly conserved among fish, including lumpfish. The transcriptome-wide analyses lay the groundwork for future research into the functional significance of these genes in regulating critical biological processes and make an important basis for development of prophylactic measure such as vaccination, which is highly needed for lumpfish since it is vulnerable for both bacterial and viral diseases.
Topics: Animals; Janus Kinases; Signal Transduction; STAT Transcription Factors; Bacteria; Perciformes; Antiviral Agents
PubMed: 37808912
DOI: 10.3389/fcimb.2023.1252744 -
Frontiers in Immunology 2023Alloimmune responses against platelet antigens, which dominantly target the major histocompatibility complex (MHC), can cause adverse reactions to subsequent platelet...
INTRODUCTION
Alloimmune responses against platelet antigens, which dominantly target the major histocompatibility complex (MHC), can cause adverse reactions to subsequent platelet transfusions, platelet refractoriness, or rejection of future transplants. Platelet transfusion recipients include individuals experiencing severe bacterial or viral infections, and how their underlying health modulates platelet alloimmunity is not well understood.
METHODS
This study investigated the effect of underlying inflammation on platelet alloimmunization by modelling viral-like inflammation with polyinosinic-polycytidylic acid (poly(I:C)) or gram-negative bacterial infection with lipopolysaccharide (LPS), hypothesizing that underlying inflammation enhances alloimmunization. Mice were pretreated with poly(I:C), LPS, or nothing, then transfused with non-leukoreduced or leukoreduced platelets. Alloantibodies and allogeneic MHC-specific B cell (allo-B cell) responses were evaluated two weeks later. Rare populations of allo-B cells were identified using MHC tetramers.
RESULTS
Relative to platelet transfusion alone, prior exposure to poly(I:C) increased the alloantibody response to allogeneic platelet transfusion whereas prior exposure to LPS diminished responses. Prior exposure to poly(I:C) had equivalent, if not moderately diminished, allo-B cell responses relative to platelet transfusion alone and exhibited more robust allo-B cell memory development. Conversely, prior exposure to LPS resulted in diminished allo-B cell frequency, activation, antigen experience, and germinal center formation and altered memory B cell responses.
DISCUSSION
In conclusion, not all inflammatory environments enhance bystander responses and prior inflammation mediated by LPS on gram-negative bacteria may in fact curtail platelet alloimmunization.
Topics: Mice; Animals; Platelet Transfusion; Lipopolysaccharides; Poly C; Mice, Inbred BALB C; Histocompatibility Antigens; Inflammation; Poly I-C
PubMed: 38146372
DOI: 10.3389/fimmu.2023.1281130 -
Behavioural Brain Research Feb 2024Calorie restriction (CR) has been shown to extend the mean and maximum lifespan in both preclinical and clinical settings. We have previously demonstrated that CR...
Calorie restriction (CR) has been shown to extend the mean and maximum lifespan in both preclinical and clinical settings. We have previously demonstrated that CR attenuates lipopolysaccharide (LPS)-induced fever and sickness behavior. CR also leads to reductions in pro-inflammatory and increases in anti-inflammatory profiles. LPS is a bacterial mimetic; however, few studies have explored this phenomenon utilizing a viral mimetic, such as polyinosinic:polycytidylic acid (poly I:C). Dose-dependently, poly I:C induced an increase in core body temperature (T), with the largest dose (5000 µg/kg) resulting in a 1.62 °C ( ± 0.23 °C) T increase at 7 h post-injection in ad libitum mice and was associated with reduced home-cage locomotor activity. We then investigated the effect of 50% CR for 28 days to attenuate fever and sickness behavior induced by a poly I:C (5000 µg/kg) viral immune challenge. CR resulted in the partial attenuation of fever and sickness behavior measures post-poly I:C. The freely fed, control mice demonstrated a 2.02 °C ( ± 0.22 °C) increase in T at 7 h post-injection compared to the CR poly I:C group which demonstrated an increase in T of 0.94 °C ( ± 0.27 °C). Locomotor patterns post-injection were different, CR mice displayed a reduction in activity during the light phase, and the control group displayed a reduction during the dark phase. CR moderately attenuated the neuroinflammatory response with a reduction in microglial density in the ventromedial nucleus of the hypothalamus. The fever and sickness behavior attenuation seen after CR may be driven by similar anti-inflammatory processes as after LPS; however, further investigation is required.
Topics: Mice; Animals; Illness Behavior; Caloric Restriction; Lipopolysaccharides; Fever; Poly I-C; Anti-Inflammatory Agents
PubMed: 37838243
DOI: 10.1016/j.bbr.2023.114715 -
Infection Aug 2023BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and...
PURPOSE
BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-α blockade on BKPyV infection.
METHODS
Urine specimens from 22 patients with BKPyV-associated nephropathy (BKPyVN) and 35 non-BKPyVN kidney transplant recipients were analyzed.
RESULTS
We demonstrated increased urinary levels of TNF-α and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-α stimulated the expression of large T antigen and viral capsid protein-1 mRNA and proteins and BKPyV promoter activity. Knockdown of TNFR1 or TNFR2 expression caused a reduction in TNF-α-stimulated viral replication. NF-κB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-κB binding site. The addition of a NF-κB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-α functionality by etanercept reduced BKPyV-stimulated expression of TNF-α, interleukin-1β (IL-1β), IL-6 and IL-8 and suppressed TNF-α-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-α, interleukin-1 β (IL-1β), IL-6 and TNFR1 and TNFR2 but the stimulated magnitude was far less than that induced by poly(I:C). This may suggest that BKPyV-mediated autocrine effect is not a major source of TNFα.
CONCLUSION
TNF-α stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target.
Topics: Humans; BK Virus; Tumor Necrosis Factor-alpha; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; NF-kappa B; Interleukin-6; Polyomavirus Infections; Inflammation
PubMed: 36512270
DOI: 10.1007/s15010-022-01962-0