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Fish & Shellfish Immunology Dec 2022Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of double-stranded RNA (dsRNA) that activates anti-infective innate immunity. The underlying mechanisms...
Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of double-stranded RNA (dsRNA) that activates anti-infective innate immunity. The underlying mechanisms are identified as targeting pattern recognition receptors and Th1-inducing. However, whether poly I:C manipulates metabolism to implement this anti-infective function is unknown. Here, GC-MS based metabolomics was used to characterize metabolic profiles induced by different doses of poly I:C. Analysis on the dose-dependent metabolomes shows that elevation of the TCA cycle and malate with the increasing dose of ploy I:C forms the most characteristic feature of the poly I:C stimulation. Exogenous malate activates the TCA cycle and elevates survival of zebrafish infected with Vibrio alginolyticus, which is related to the elevated expression of il-1b, il-6, il-8, tnf-a, and c3b. These results reveal a previously unknown regulation of poly I:C that boosts the TCA cycle to enhance innate immunity against bacterial infection.
Topics: Animals; Poly I-C; Malates; Zebrafish; Immunity, Innate; RNA, Double-Stranded; Bacterial Infections
PubMed: 36210004
DOI: 10.1016/j.fsi.2022.09.064 -
The Urologic Clinics of North America Nov 2020Relatively simple, synthetic, double-stranded RNAs can be powerful viral pathogen-associated molecular pattern (PAMP) mimics, inducing a panoply of antiviral and... (Review)
Review
Relatively simple, synthetic, double-stranded RNAs can be powerful viral pathogen-associated molecular pattern (PAMP) mimics, inducing a panoply of antiviral and antitumor responses that act at multiple stages of host defense. Their mechanisms of action and uses are beginning to be understood, alone, in combination with other therapeutics, or as novel PAMP-adjuvants providing the critical danger signal that has been missing from most cancer and other modern vaccines. Dose, timing, route of administration combinations, and other clinical variables can have a critical impact on immunogenicity. This article reviews advances in the use of polyinosinic-polycytidylic acid and derivatives, in particular poly-ICLC.
Topics: Adjuvants, Immunologic; Cancer Vaccines; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Humans; Immunologic Factors; Male; Pathogen-Associated Molecular Pattern Molecules; Poly I-C; Polylysine; Prostatic Neoplasms; RNA, Double-Stranded
PubMed: 33446322
DOI: 10.1016/j.ucl.2020.10.003 -
Pharmacology & Therapeutics May 2015Increasing epidemiological and experimental evidence implicates gestational infections as one important factor involved in the pathogenesis of several neuropsychiatric... (Review)
Review
Increasing epidemiological and experimental evidence implicates gestational infections as one important factor involved in the pathogenesis of several neuropsychiatric disorders. Corresponding preclinical model systems based upon maternal immune activation (MIA) by treatment of the pregnant female have been developed. These MIA animal model systems have been successfully used in basic and translational research approaches, contributing to the investigation of the underlying pathophysiological mechanisms at the molecular, cellular and behavioral levels. The present article focuses on the application of a specific MIA rodent paradigm, based upon treatment of the gestating dam with the viral mimic polyinosinic-polycytidilic acid (Poly(I:C)), a synthetic analog of double-stranded RNA (dsRNA) which activates the Toll-like receptor 3 (TLR3) pathway. Important advantages and constraints of this animal model will be discussed, specifically in light of gestational infection as one vulnerability factor contributing to the complex etiology of mood and psychotic disorders, which are likely the result of intricate multi-level gene×environment interactions. Improving our currently incomplete understanding of the molecular pathomechanistic principles underlying these disorders is a prerequisite for the development of alternative therapeutic approaches which are critically needed in light of the important drawbacks and limitations of currently available pharmacological treatment options regarding efficacy and side effects. The particular relevance of the Poly(I:C) MIA model for the discovery of novel drug targets for symptomatic and preventive therapeutic strategies in mood and psychotic disorders is highlighted in this review article.
Topics: Animals; Disease Models, Animal; Drug Discovery; Humans; Mental Disorders; Models, Immunological; Poly I-C
PubMed: 25562580
DOI: 10.1016/j.pharmthera.2015.01.001 -
The International Journal of... Feb 2022Exposure to polyriboinosinic-polyribocytidylic acid (Poly I:C) in pregnant rats has been reported to cause schizophrenia-like behaviors and abnormal neurotransmissions...
BACKGROUND
Exposure to polyriboinosinic-polyribocytidylic acid (Poly I:C) in pregnant rats has been reported to cause schizophrenia-like behaviors and abnormal neurotransmissions in adult, particularly male, offspring. However, what is less well understood are the effects of maternal Poly I:C exposure on adolescent behaviors and neurotransmission in female juvenile rats.
METHODS
Female adolescent Poly I:C offspring were constructed by treating with 5 mg/kg Poly I:C on timed pregnant rats (gestation day 15). A battery of behavioral tests was conducted during postnatal day 35-60. Neurotransmitter receptors and inflammation markers in brain regions were evaluated by RT-qPCR on postnatal day 60.
RESULTS
Open field, elevated plus maze, and forced swimming tests revealed that prenatal Poly I:C exposure led to elevated anxiety-like and depression-like behaviors in female adolescent offspring. Deficits in pre-pulse inhibition and social interaction were also observed. However, the Poly I:C rats had better performance than the controls in the novel object recognition memory test, which demonstrated a behavioral phenotype with improved cognitive function. Prenatal Poly I:C exposure caused brain region-specific elevation of the P2X7 receptor- and NF-κB-NLRP3-IL-1β inflammatory signaling in female juvenile rats. Prenatal Poly I:C exposure decreased expression of GABAA receptor subunits Gabrb3 in the prefrontal cortex and Gabrb1 and dopamine D2 receptor in the hippocampus, but increased NMDA receptor subunit Grin2a in the prefrontal cortex, 5-HT2A in the hippocampus, and Gabrb3 and D2 receptor in the nucleus accumben.
CONCLUSIONS
Prenatal Poly I:C challenge causes behavioral deficits and brain-specific neurotransmission changes via elevated neuroinflammation responses in female adolescent offspring rats.
Topics: Animals; Behavior, Animal; Brain; Cognition; Disease Models, Animal; Female; Hippocampus; Memory, Short-Term; Neuroinflammatory Diseases; Poly I-C; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Prepulse Inhibition; Rats; Receptors, Dopamine D2; Schizophrenia; Synaptic Transmission
PubMed: 34893855
DOI: 10.1093/ijnp/pyab087 -
American Journal of Physiology.... Feb 2022A prominent health issue nowadays is the COVID-19 pandemic, which poses acute risks to human health. However, the long-term health consequences are largely unknown and... (Review)
Review
A prominent health issue nowadays is the COVID-19 pandemic, which poses acute risks to human health. However, the long-term health consequences are largely unknown and cannot be neglected. An especially vulnerable period for infection is pregnancy, when infections could have long-term health effect on the child. Evidence suggests that maternal immune activation (MIA) induced by either bacteria or viruses presents various effects on the offspring, leading to adverse phenotypes in many organ systems. This review compares the mechanisms of bacterial and viral MIA and the possible long-term outcomes for the offspring by summarizing the outcome in animal LPS and Poly I:C models. Both models are activated immune responses mediated by Toll-like receptors. The outcomes for MIA offspring include neurodevelopment, immune response, circulation, metabolism, and reproduction. Some of these changes continue to exist until later life. Besides different doses and batches of LPS and Poly I:C, the injection day, administration route, and also different animal species influence the outcomes. Here, we specifically aim to support colleagues when choosing their animal models for future studies.
Topics: Bacterial Infections; COVID-19; Female; Humans; Lipopolysaccharides; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; SARS-CoV-2
PubMed: 34874190
DOI: 10.1152/ajpregu.00087.2021 -
Poultry Science Aug 2021Exosomes are small membrane vesicles that contain proteins and nucleic acids derived from secretory cells and mediate intracellular communication. Immune cell-derived...
Exosomes are small membrane vesicles that contain proteins and nucleic acids derived from secretory cells and mediate intracellular communication. Immune cell-derived exosomes regulate immune responses and gene expression of recipient cells. Macrophages recognize viral dsRNA via Toll-like receptor 3, thereby inducing the activation of transcription factors such as interferon regulatory factor 3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In this study, we aimed to identify the immunomodulatory functions of exosomes derived from chicken macrophages (HD11) stimulated with polyinosinic-polycytidylic acid (poly[I:C]); exosomes were then delivered into HD11 cells and CU91 chicken T cells. Exosomes purified from poly(I:C)-activated macrophages stimulated the expression of type I interferons, proinflammatory cytokines, anti-inflammatory cytokines, and chemokines in HD11 and CU91 cells. Moreover, poly(I:C)-stimulated exosomes induced the NF-κB signaling pathway by phosphorylating TAK1 and NF-κB1. Therefore, we suggest that after the activation of Toll-like receptor 3 ligands following infection with dsRNA virus, chicken macrophages regulate the immune response of naive macrophages and T cells through the NF-κB signaling pathway. Furthermore, poly(I:C)-activated exosomes can be potentially utilized as immunostimulators.
Topics: Animals; Chickens; Exosomes; Immunity; Macrophages; NF-kappa B; Poly I-C
PubMed: 34174563
DOI: 10.1016/j.psj.2021.101247 -
Biochemical and Biophysical Research... Aug 2021Neutrophil extracellular traps (NETs) are extracellular webs of DNA, histones and granular contents that are released by neutrophils to control infections. However, NETs...
Neutrophil extracellular traps (NETs) are extracellular webs of DNA, histones and granular contents that are released by neutrophils to control infections. However, NETs that is not properly regulated can propagate inflammation and thrombosis. It was recognized that viruses can induce NETs. As a synthetic analog of viral double-stranded (ds) RNA, polyinosinic-polycytidylic acid [poly(I:C)] is known to induce inflammation and thrombosis. However, whether and how poly(I:C) modulates NETs remains unclear. Here, we have demonstrated that poly(I:C) induced extracellular DNA traps in human neutrophils in a dose-dependent manner. Further, poly(I:C) or dsRNA virus elevated the levels of myeloperoxidase-DNA complexes and citrullinated histone H3, which are specific markers of NETs, in both neutrophil supernatants and mouse plasma. Interestingly, a potent peptidylarginine deiminase 4 (PAD4) inhibitor, BB-CL-Amidine (BB-CLA) or PAD4 knockdown effectively prevented poly(I:C)-induced NETs formation and release. In addition, BB-CLA abrogated poly(I:C)-triggered neutrophil activation and infiltration, and vascular permeability in lungs. BB-CLA also attenuated poly(I:C)-induced thrombocytopenia in circulation, fibrin deposition and thrombus formation in tissues. Taken together, these results suggest that viral mimetic poly(I:C) may induce NETs-dependent inflammation and thrombosis through PAD4, and that inhibiting PAD4 may become a good strategy to protect against viral infection-caused inflammation/thrombosis-related pathological conditions of diseases.
Topics: Amidines; Animals; Cells, Cultured; Chlorocebus aethiops; Extracellular Traps; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Neutrophil Activation; Neutrophils; Poly I-C; Protein-Arginine Deiminase Type 4; Thrombosis
PubMed: 34098313
DOI: 10.1016/j.bbrc.2021.05.091 -
Virology Feb 2023Virus-like particles (VLPs) are extremely potent, safe, and serviceable vaccine platforms. Good assembly efficiency of VLPs is the key to reducing vaccine production...
Virus-like particles (VLPs) are extremely potent, safe, and serviceable vaccine platforms. Good assembly efficiency of VLPs is the key to reducing vaccine production costs and eliciting a robust immune response. This study adopted CpG and Poly (I:C) as scaffolds to facilitate the assembly of foot-and-mouth disease virus (FMDV) VLPs in vitro. The VLPs and the co-assembly products were characterized by particle size, zeta potential, gel retardation measurement, nuclease digestion experiments, size-exclusion chromatography, transmission electron microscopy and circular dichroism analysis. Our results indicated the successful encapsulation of CpG and Poly (I:C) inside VLPs without any effect on shape or size. Vaccination in mice also elicited a robust immune response. This study demonstrated that CpG and Poly (I:C) improved the efficiency of FMDV VLPs assembly and enhanced immune response, further proposing a new idea for improving the efficiency of VLPs assembly and enriching the in vitro VLPs assembly strategies.
Topics: Animals; Mice; Foot-and-Mouth Disease Virus; Foot-and-Mouth Disease; Poly I-C; Vaccination; Immunity; Vaccines, Virus-Like Particle; Antibodies, Viral
PubMed: 36623353
DOI: 10.1016/j.virol.2022.12.016 -
Viruses Nov 2023Type I and III interferons are among the most important antiviral mediators. Increased susceptibility to infections has been described as being associated with impaired...
Type I and III interferons are among the most important antiviral mediators. Increased susceptibility to infections has been described as being associated with impaired interferon response in asthmatic patients. In this work, we focused on the modulation of interferon dysfunction after the rhinovirus infection of airway epithelial cells. Therefore, we tested polyinosinic:polycytidylic acid (poly I:C), a TLR3 agonist, as a possible preventive pre-treatment to improve this anti-viral response. In our human study on asthma, we found a deficiency in interferon levels in the nasal epithelial cells (NEC) from asthmatics at homeostatic level and after RV infection, which might contribute to frequent airway infection seen in asthmatic patients compared to healthy controls. Finally, pre-treatment with the immunomodulatory substance poly I:C before RV infection restored IFN responses in airway epithelial cells. Altogether, we consider poly I:C pre-treatment as a promising strategy for the induction of interferon response prior to viral infections. These results might help to improve current therapeutic strategies for allergic asthma exacerbations.
Topics: Humans; Interferons; Asthma; Poly I-C; Epithelial Cells; Antiviral Agents; Rhinovirus; Picornaviridae Infections
PubMed: 38140569
DOI: 10.3390/v15122328 -
Frontiers in Immunology 2022Adjuvants are essential for vaccine development, especially subunit-based vaccines such as those containing recombinant proteins. Increasing the knowledge of the immune...
Adjuvants are essential for vaccine development, especially subunit-based vaccines such as those containing recombinant proteins. Increasing the knowledge of the immune response mechanisms generated by adjuvants should facilitate the formulation of vaccines in the future. The present work describes the immune phenotypes induced by Poly (I:C) and Montanide ISA 720 in the context of mice immunization with a recombinant protein based on the circumsporozoite protein (PvCSP) sequence. Mice immunized with the recombinant protein plus Montanide ISA 720 showed an overall more robust humoral response, inducing antibodies with greater avidity to the antigen. A general trend for mixed Th1/Th2 inflammatory cytokine profile was increased in Montanide-adjuvanted mice, while a balanced profile was observed in Poly (I:C)-adjuvanted mice. Montanide ISA 720 induced a gene signature in B lymphocytes characteristic of heme biosynthesis, suggesting increased differentiation to Plasma Cells. On the other hand, Poly (I:C) provoked more perturbations in T cell transcriptome. These results extend the understanding of the modulation of specific immune responses induced by different classes of adjuvants, and could support the optimization of subunit-based vaccines.
Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Animals; Antibodies, Protozoan; Immune System; Immunity; Mice; Mineral Oil; Poly I-C; Recombinant Proteins
PubMed: 35844531
DOI: 10.3389/fimmu.2022.910022