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Microbiology and Immunology May 2013Not-self or denatured nucleic acids are recognized by pattern recognition receptors localized mainly in endosomes and cytoplasm, such as Toll-like receptor (TLR) 3,... (Review)
Review
Not-self or denatured nucleic acids are recognized by pattern recognition receptors localized mainly in endosomes and cytoplasm, such as Toll-like receptor (TLR) 3, TLR7, TLR9, retinoic acid-inducible gene-I, DNA-dependent activator of IFN-regulatory factors and other receptors. The binding of polyriboinosinic:polyribocytidylic acid (poly I:C), a synthetic dsRNA that robustly induces type I interferon, to a putative cell-surface receptor on a rabbit kidney cell line, RK13, has been analyzed by the authors and RK13 cells found to capture poly I:C in a specific fashion with sufficient affinity. These findings suggest that an alternative receptor to poly I:C participates in the induction of type 1 interferon, which localizes on cell surfaces. Although the nature of this molecule has not yet been identified, accumulating evidence has led the present authors to speculate that there are undefined classes of RNA-recognition molecules on cell surfaces and that these are unlikely to be categorized as previously reported dsRNA receptors. Although many years have passed since this possibility was first reported by the present authors, it remains attractive. In this article, previously reported cell-surface dsRNA receptors are reviewed in comparison with other receptors reported to date that are firmly involved in the innate immune-sensing of nucleic acids.
Topics: Animals; Cell Line; Interferons; Poly I-C; RNA, Double-Stranded; Rabbits; Receptors, Immunologic
PubMed: 23668603
DOI: 10.1111/1348-0421.12050 -
Iranian Journal of Immunology : IJI Sep 2017Cytosolic double-stranded RNA (dsRNA) is an important 'molecular signature' for the detection of intracellular viral infections. Although intracellular dsRNA is a known...
BACKGROUND
Cytosolic double-stranded RNA (dsRNA) is an important 'molecular signature' for the detection of intracellular viral infections. Although intracellular dsRNA is a known potent inducer of apoptosis, the optimal time and dose for the onset of dsRNA-mediated apoptosis have not been studied in detail.
OBJECTIVE
To perform an accurate temporal assessment of the cell death responses in dsRNA-dependent cytotoxicity.
METHODS
Poly I:C (PIC), a synthetic dsRNA molecule was delivered intracellularly into J774.1 and RAW264.7 murine macrophages via electroporation. Cell viability was measured using the MTT assay and apoptosis was determined by sub-G0/G1 DNA content using flow cytometry.
RESULTS
Loss of cell viability was seen as early as 3h post-electroporation of macrophages. A significant increase in the sub-G0/G1 DNA content consistent with apoptosis was observed in PIC-electroporated macrophages as early as 3h post electroporation.
CONCLUSION
Intracellular PIC delivery induces rapid macrophage cell death.
Topics: Animals; Cell Cycle; Cell Death; Cell Survival; DNA; Electroporation; Macrophages; Mice; Poly I-C; RAW 264.7 Cells; RNA, Double-Stranded
PubMed: 28919588
DOI: No ID Found -
Brain, Behavior, and Immunity Jul 2021Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings. However, the mechanisms underlying its success are not understood....
Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings. However, the mechanisms underlying its success are not understood. Incorporating components of EE protocols into our animal models allows for the exploration of these mechanisms and their role in mitigation. Using a mouse model of maternal immune activation (MIA), the present study explored disruptions in social behavior and associated hypothalamic pituitary adrenal (HPA) axis functioning, and whether a supportive environment could prevent these effects. We show that prenatal immune activation of toll-like receptor 3, by the viral mimetic polyinosinic-polycytidylic acid (poly(I:C)), led to disrupted maternal care in that dams built poorer quality nests, an effect corrected by EE housing. Standard housed male and female MIA mice engaged in higher rates of repetitive rearing and had lower levels of social interaction, alongside sex-specific expression of several ventral hippocampal neural stress markers. Moreover, MIA males had delayed recovery of plasma corticosterone in response to a novel social encounter. Enrichment housing, likely mediated by improved maternal care, protected against these MIA-induced effects. We also evaluated c-Fos immunoreactivity associated with the novel social experience and found MIA to decrease neural activation in the dentate gyrus. Activation in the hypothalamus was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. These data demonstrate that augmentation of the environment supports parental care and offspring safety/security, which can offset effects of early health adversity by buffering HPA axis dysregulation. Our findings provide further evidence for the viability of EE interventions in maternal and pediatric settings.
Topics: Animals; Child; Female; Hippocampus; Humans; Hypothalamo-Hypophyseal System; Male; Pituitary-Adrenal System; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Social Behavior
PubMed: 33766701
DOI: 10.1016/j.bbi.2021.03.018 -
The Journal of Investigative Dermatology Jul 2023Actinic keratoses and cutaneous squamous cell carcinomas are associated with infections with human papillomavirus of genus beta (betaHPV) in immunosuppressed patients....
Actinic keratoses and cutaneous squamous cell carcinomas are associated with infections with human papillomavirus of genus beta (betaHPV) in immunosuppressed patients. To date, targeted therapy against betaHPV-associated skin cancer does not exist because of the large number of betaHPV without defined high-risk types. In this study, we hypothesized that the activation of innate antiviral immunity in the skin, asymptomatically infected with betaHPV, induces an antitumor response by in situ autovaccination and prevents the formation of betaHPV-associated skin cancer. To test this, we used the preclinical keratin-14-HPV8 transgenic mouse model, which develops skin tumors after mechanical wounding. Remarkably, treatment with the antiviral immune response activating polyinosinic-polycytidylic acid (poly[I:C]) completely prevented cutaneous tumor growth. The induction of the IFN-induced genes Cxcl10 and Ifit1 by poly(I:C) depended on MDA5 activation. Increased numbers of total and activated CD4 and CD8 T cells were detected in poly(I:C)-treated skin. T cells were found in the skin of poly(I:C)-treated mice but not in the skin tumors of untreated mice. T-cell depletion showed a predominant role of CD4 T cells in poly(I:C)-mediated tumor prevention. Our findings identify the MDA5 ligand poly(I:C) as a promising candidate for in situ autovaccination approaches, which might serve as a treatment strategy against betaHPV-related skin diseases.
Topics: Humans; Mice; Animals; Mice, Transgenic; Poly I-C; Skin Neoplasms; Skin; Antiviral Agents
PubMed: 36584911
DOI: 10.1016/j.jid.2022.12.007 -
PloS One 2011α active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells...
α active specific immunotherapy aims at stimulating the host's immune system to recognize and eradicate malignant cells. The concomitant activation of dendritic cells (DC) and natural killer (NK) cells is an attractive modality for immune-based therapies. Inducing immunogenic cell death to facilitate tumor cell recognition and phagocytosis by neighbouring immune cells is of utmost importance for guiding the outcome of the immune response. We previously reported that acute myeloid leukemic (AML) cells in response to electroporation with the synthetic dsRNA analogue poly(I:C) exert improved immunogenicity, demonstrated by enhanced DC-activating and NK cell interferon-γ-inducing capacities. To further invigorate the potential of these immunogenic tumor cells, we explored their effect on the phagocytic and cytotoxic capacity of DC and NK cells, respectively. Using single-cell analysis, we assessed these functionalities in two- and three-party cocultures. Following poly(I:C) electroporation AML cells become highly susceptible to NK cell-mediated killing and phagocytosis by DC. Moreover, the enhanced killing and the improved uptake are strongly correlated. Interestingly, tumor cell killing, but not phagocytosis, is further enhanced in three-party cocultures provided that these tumor cells were upfront electroporated with poly(I:C). Altogether, poly(I:C)-electroporated AML cells potently activate DC and NK cell functions and stimulate NK-DC cross-talk in terms of tumor cell killing. These data strongly support the use of poly(I:C) as a cancer vaccine component, providing a way to overcome immune evasion by leukemic cells.
Topics: Dendritic Cells; Electroporation; Fluorescent Dyes; Humans; Killer Cells, Natural; Leukemia, Myeloid, Acute; Phagocytosis; Poly I-C
PubMed: 21698118
DOI: 10.1371/journal.pone.0020952 -
Genes Jul 2023Toll-like receptor (TLR) signaling is conserved between fish and mammals, except for TLR4, which is absent in most fish. In the present study, we aimed to evaluate...
Toll-like receptor (TLR) signaling is conserved between fish and mammals, except for TLR4, which is absent in most fish. In the present study, we aimed to evaluate whether TLR4 is expressed in (). The and were cloned and identified, and their tissue distribution was examined. The cDNA encoding and complete coding sequences (CDS) were identified and cloned. Additionally, we examined the expression levels of seven (, , , , , , and ), as well as and in the liver, head kidney, hindgut, and spleen of , after intraperitoneal injection of polyinosinic-polycytidylic acid (poly (I:C)). The TLR2 and TLR4 shared amino acid sequence identity of 42.15-96.21% and 36.21-93.58%, respectively, with sequences from other vertebrates. and were expressed in all tissues examined, particularly in immune-related tissues. Poly (I:C) significantly upregulated most of the genes evaluated in the four immune organs compared with the PBS-control ( < 0.05); expression of these different genes was tissue-specific. Our findings demonstrate that TLR2 and TLR4 are expressed in and that poly (I:C) affects the expression of nine TLR-related genes, which are potentially involved in antiviral immunity or mediating pathological processes with differential kinetics. This will contribute to a better understanding of the roles of these TLR-related genes in antiviral immunity.
Topics: Animals; Toll-Like Receptor 2; Poly I-C; Toll-Like Receptor 4; Toll-Like Receptors; Cyprinidae; Cloning, Molecular; Mammals
PubMed: 37510293
DOI: 10.3390/genes14071388 -
MBio Mar 2020Viral diseases cause significant losses in aquaculture. Prophylactic measures, such as immune priming, are promising control strategies. Treatment of the Pacific oyster...
Viral diseases cause significant losses in aquaculture. Prophylactic measures, such as immune priming, are promising control strategies. Treatment of the Pacific oyster () with the double-stranded RNA analog poly(I·C) confers long-term protection against infection with ostreid herpesvirus 1, the causative agent of Pacific oyster mortality syndrome. In a recent article in , Lafont and coauthors (M. Lafont, A. Vergnes, J. Vidal-Dupiol, J. de Lorgeril, et al., mBio 11:e02777-19, 2020, https://doi.org/10.1128/mBio.02777-19) characterized the transcriptome of oysters treated with poly(I·C). This immune stimulator induced genes related to the interferon and apoptosis pathways. This response overlaps the response to viral infection, and high expression levels of potential effector genes are maintained for up to 4 months. This work opens the door to characterization of the phenomena of immune priming in a poorly studied invertebrate model. It also highlights the importance of interferon-like responses for invertebrate antiviral immunity.
Topics: Animals; Antiviral Agents; Crassostrea; Poly I-C; RNA, Double-Stranded
PubMed: 32209685
DOI: 10.1128/mBio.00407-20 -
Scientific Reports Jul 2023Toll-like receptor (TLR) agonists improve vaccine immunogenicity and efficacy, but they are currently unlicensed as adjuvants in influenza vaccines. This study aimed to...
Toll-like receptor (TLR) agonists improve vaccine immunogenicity and efficacy, but they are currently unlicensed as adjuvants in influenza vaccines. This study aimed to investigate whether a combination of monophosphoryl lipid A (MPL, a TLR4 agonist) and polyriboinosinic polyribocytidylic acid (poly I:C, a TLR3 agonist) can enhance the protective efficacy of an inactivated A/Puerto Rico/8/1934 (A/PR8) H1N1 influenza vaccine against homologous influenza infection and minimize illness outcomes. Results showed that combination MPL and poly I:C adjuvanted influenza vaccination increased the production of antigen-specific antibodies, decreased the levels of cytokines and cellular infiltrates at the infection sites, and induced significant memory T and B cell responses in mice. The results of this study suggest that the combination of MPL and poly I:C can be developed into a possible adjuvant for enhancing the efficacy of influenza vaccines.
Topics: Animals; Mice; Humans; Influenza Vaccines; Influenza, Human; Poly I-C; Influenza A Virus, H1N1 Subtype; Antibodies, Viral; Adjuvants, Immunologic; Immunity; Adjuvants, Pharmaceutic; Mice, Inbred BALB C
PubMed: 37507413
DOI: 10.1038/s41598-023-39210-6 -
International Journal of Molecular... Apr 2023The yellow drum () is a marine teleost fish with strong disease resistance, yet the understanding of its immune response and key functional genes is fragmented. Here,...
The yellow drum () is a marine teleost fish with strong disease resistance, yet the understanding of its immune response and key functional genes is fragmented. Here, RNA-Seq was used to investigate the regulation pathways and genes involved in the immune response to infection with lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (poly (I:C)) on the spleen of the yellow drum. There were fewer differentially expressed genes (DEGs) in the LPS-infected treatment group at either 6 or 48 h. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEGs were mainly significantly enriched in c5-branching dibasic acid metabolic and complement and coagulation cascades pathways. The yellow drum responded more strongly to poly (I:C) infection, with 185 and 521 DEGs obtained under 6 and 48 h treatments, respectively. These DEGs were significantly enriched in the Toll-like receptor signaling pathway, RIG-I-like receptor signaling pathway, Jak-STAT signaling pathway, NOD-like signaling pathway, and cytokine-cytokine receptor interaction. The key functional genes in these pathways played important roles in the immune response and maintenance of immune system homeostasis in the yellow drum. Weighted gene co-expression network analysis (WGCNA) revealed several important hub genes. Although the functions of some genes have not been confirmed, our study still provides significant information for further investigation of the immune system of the yellow drum.
Topics: Animals; Lipopolysaccharides; Spleen; Poly I-C; Gene Expression Profiling; Immunity; Perciformes; Transcriptome
PubMed: 37175446
DOI: 10.3390/ijms24097735 -
PloS One 2023Early neuropathology mechanisms in neurodevelopmental disorders are partially understood because routine anatomical magnetic resonance imaging (MRI) cannot detect subtle...
The combined use of DTI and MR elastography for monitoring microstructural changes in the developing brain of a neurodevelopmental disorder model: Poly (I:C)-induced maternal immune-activated rats.
Early neuropathology mechanisms in neurodevelopmental disorders are partially understood because routine anatomical magnetic resonance imaging (MRI) cannot detect subtle brain microstructural changes in vivo during postnatal development. Therefore, we investigated the potential value of magnetic resonance elastography (MRE) and diffusion tensor imaging (DTI) in a rat model of neurodevelopmental disorder induced by maternal immune activation. We studied 12 offspring of mothers injected with polyriboinosinic-polyribocytidylic acid (poly (I:C), 4 mg/kg) on gestational day 15, plus 8 controls. T2-weighted anatomical MR images, MRE (800 Hz) and DTI (30 gradient directions, b = 765.8 s/mm2, 5 images, b = 0 s/mm2) were collected when the rats were 4 and 10 weeks old, and results were compared with histological analysis performed at week 10. Ventricles were ~1.4 fold larger from week 4 in poly (I:C) rats than in controls. No other morphological abnormalities were detected in poly(I:C) rats. At week 4, larger ventricles were correlated with lower external capsule fractional anisotropy and internal capsule radial diffusion (Pearson, r = -0.53, 95% confidence intervals (CI) [-0.79 to -0.12], and r = -0.45, 95% CI [-0.74 to -0.01], respectively). The mean and radial diffusion of the corpus callosum, the mean and axial diffusion of the internal capsule and the radial diffusion properties in the external capsule increased with age for poly (I:C) rats only (Sidak's comparison, P<0.05). Cortical stiffness did not increase with age in poly (I:C) rats, in contrast with controls (Sidak's comparison, P = 0.005). These temporal variations probably reflected abnormal myelin content, decreased cell density and microglia activation observed at week 10 after histological assessment. To conclude, MRE and DTI allow monitoring of abnormal brain microstructural changes in poly (I:C) rats from week 4 after birth. This suggests that both imaging techniques have the potential to be used as complementary imaging tools to routine anatomical imaging to assist with the early diagnosis of neurodevelopmental disorders and provide new insights into neuropathology.
Topics: Rats; Animals; Diffusion Tensor Imaging; Elasticity Imaging Techniques; Poly I-C; Brain; Magnetic Resonance Imaging; Anisotropy; Diffusion Magnetic Resonance Imaging
PubMed: 36638122
DOI: 10.1371/journal.pone.0280498