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https://www.readbyqxmd.com/read/28808328/light-guided-in-vivo-activation-of-innate-immune-cells-with-photocaged-tlr-2-6-agonist
#1
Keun Ah Ryu, Bethany McGonnigal, Troy Moore, Tawnya Kargupta, Rock J Mancini, Aaron P Esser-Kahn
The complexity of the immune system creates challenges in exploring its importance and robustness. To date, there have been few techniques developed to manipulate individual components of the immune system in an in vivo environment. Here we show a light-based dendritic cell (DC) activation allowing spatial and temporal control of immune activation in vivo. Additionally, we show time dependent changes in RNA profiles of the draining lymph node, suggesting a change in cell profile following DC migration and indicating that the cells migrating have been activated towards antigen presentation...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28804955/3m-052-as-an-adjuvant-for-a-plga-microparticle-based-leishmania-donovani-recombinant-protein-vaccine
#2
Qian Wang, Meagan A Barry, Christopher A Seid, Elissa M Hudspeth, C Patrick McAtee, Michael J Heffernan
It is believed that an effective vaccine against leishmaniasis will require a T helper type 1 (TH 1) immune response. In this study, we investigated the adjuvanticity of the Toll-like receptor (TLR) 7/8 agonist 3M-052 in combination with the Leishmania donovani 36-kDa nucleoside hydrolase recombinant protein antigen (NH36). NH36 and 3M-052 were encapsulated in separate batches of poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs). The loading efficiency for NH36 was 83% and for 3M-052 was above 95%. In vitro stimulation of bone marrow-derived dendritic cells, measured by IL-12 secretion, demonstrated that 3M-052 (free or MP-formulated) had a concentration-dependent immunostimulatory effect with an optimum concentration of 2 µg/mL...
August 14, 2017: Journal of Biomedical Materials Research. Part B, Applied Biomaterials
https://www.readbyqxmd.com/read/28800975/exopolysaccharides-from-lactobacillus-delbrueckii-oll1073r-1-modulate-innate-antiviral-immune-response-in-porcine-intestinal-epithelial-cells
#3
Paulraj Kanmani, Leonardo Albarracin, Hisakazu Kobayashi, Hikaru Iida, Ryoya Komatsu, A K M Humayun Kober, Wakako Ikeda-Ohtsubo, Yoshihito Suda, Hisashi Aso, Seiya Makino, Hiroshi Kano, Tadao Saito, Julio Villena, Haruki Kitazawa
Previous studies demonstrated that the extracellular polysaccharides (EPSs) produced by Lactobacillus delbrueckii OLL1073R-1 (LDR-1) improve antiviral immunity, especially in the systemic and respiratory compartments. However, it was not studied before whether those EPSs are able to beneficially modulate intestinal antiviral immunity. In addition, LDR-1-host interaction has been evaluated mainly with immune cells while its interaction with intestinal epithelial cells (IECs) was not addressed before. In this work, we investigated the capacity of EPSs from LDR-1 to modulate the response of porcine IECs (PIE cells) to the stimulation with the Toll-like receptor (TLR)-3 agonist poly(I:C) and the role of TLR2, TLR4, and TLR negative regulators in the immunoregulatory effect...
August 8, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28796783/myd88-contribution-to-ocular-surface-homeostasis
#4
Rose Y Reins, Justin Courson, Carolina Lema, Rachel L Redfern
The cornea must maintain homeostasis, enabling rapid response to injury and microbial insult, to protect the eye from insult and infection. Toll-like receptors (TLRs) are critical to this innate immune response through the recognition and response to pathogens. Myeloid differentiation primary response (MyD88) is a key signaling molecule necessary for Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R)-mediated immune defense and has been shown to be necessary for corneal defense during infection. Here, we examined the intrinsic role of TLR signaling in ocular surface tissues by determining baseline levels of inflammatory mediators, the response to mechanical stimuli, and corneal infection in MyD88-deficient mice (MyD88-/-)...
2017: PloS One
https://www.readbyqxmd.com/read/28795258/lipopolysaccharide-aggravated-doi-induced-tourette-syndrome-elaboration-for-recurrence-of-tourette-syndrome
#5
Long Hongyan, Si Zhenyang, Wang Chunyan, Pan Qingqing
Tourette syndrome (TS) is a neurological disorder characterized by highest familial recurrence rate among neuropsychiatric diseases with complicated inheritance. Recurrence of Tourette syndrome was frequently observed in clinical. Unexpectedly, the mechanism of recurrence of Tourette syndrome was failure to elucidate. Here, we first shown that lipopolysaccharide(LPS) may played an important role in the recurrence of Tourette syndrome. The TS model in rats was induced by DOI (the selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl) -2- aminopropane)...
August 9, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/28783513/platelet-toll-like-receptor-tlr-expression-and-tlr-mediated-platelet-activation-in-acute-myocardial-infarction
#6
Kathryn E Hally, Anne C La Flamme, Peter D Larsen, Scott A Harding
Both platelets and Toll-like receptors (TLRs) contribute to acute myocardial infarction (AMI). Platelet activation can occur post-AMI and despite treatment with anti-platelet therapy. TLRs may represent an alternative platelet activation pathway, although the role of platelet-TLRs in AMI is poorly characterized. The aim of this study was to examine platelet-TLR expression and TLR-mediated platelet activation in healthy and AMI subjects. Here, we report that platelets from AMI patients exhibit upregulation of some, but not other, TLRs...
August 1, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28780192/a-novel-hpv-prophylactic-peptide-vaccine-designed-by-immunoinformatics-and-structural-vaccinology-approaches
#7
Manica Negahdaripour, Mahboobeh Eslami, Navid Nezafat, Nasim Hajighahramani, Mohammad Bagher Ghoshoon, Eskandar Shoolian, Ali Dehshahri, Nasrollah Erfani, Mohammad Hossein Morowvat, Younes Ghasemi
Human papillomavirus (HPV)-caused cervical cancer is the fourth common female cancer globally. Despite availability of three effective vaccines in market, development of HPV prophylactic vaccines is still pursued due to affordability issues and type-restricted protection of the marketed vaccines. Investigational second generation prophylactic HPV vaccines are mostly exploiting epitopes from the virus minor capsid protein (L2), which despite many advantages suffer from low immunogenicity, a common problem of epitope vaccines...
August 2, 2017: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/28776644/glucocorticoids-downregulate-tlr4-signaling-activity-via-its-direct-targeting-by-mir-511-5p
#8
Graziella Curtale, Tiziana A Renzi, Lorenzo Drufuca, Marcello Rubino, Massimo Locati
Endotoxin tolerance assures proper regulation of the TLR4 signaling pathway and avoids uncontrolled inflammation, limiting tissue damage and endotoxin shock development. Though underlying molecular mechanisms are still undefined, evidence indicates the involvement of microRNAs, which represent a new layer of regulation of inflammatory pathways. Here we report that LPS and other inflammatory stimuli repress miR-511-5p expression in human monocytes, while anti-inflammatory stimuli, such as TGFβ and glucocorticoids, have the opposite effect...
August 4, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28765651/cd14-is-critical-for-tlr2-mediated-m1-macrophage-activation-triggered-by-n-glycan-recognition
#9
Thiago Aparecido da Silva, André L V Zorzetto-Fernandes, Nerry T Cecílio, Aline Sardinha-Silva, Fabrício Freitas Fernandes, Maria Cristina Roque-Barreira
Agonist interaction with Toll-like receptors (TLRs) induces T cell-mediated immunity, which is effective against intracellular pathogens. Consequently, TLR agonists are being tried as immunomodulatory agents. The lectin ArtinM targets TLR2 N-glycans on macrophages, induces cytokines production, and promotes T helper-1 immunity, a process that culminates in resistance to several parasitic and fungal infections in vivo. Because co-receptors influence agonist binding to TLRs, we investigated whether CD14 is required for macrophage activation induced by ArtinM...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28739303/cpg-oligonucleotides-increase-hbv-specific-cytokine-responses-in-whole-blood-and-enhance-cytokine-release-assay-sensitivity
#10
Werner Dammermann, Julia Dornbrack, Katharina Bröker, Frank Bentzien, Stefan Lüth
BACKGROUND: Chronic hepatitis B leads to liver cirrhosis and hepatocellular carcinoma. To develop a therapeutic vaccine for chronic hepatitis B patients it is necessary to assess cellular immune responses to hepatitis B virus (HBV) antigens. We investigated the potential of toll-like receptor (TLR) 9 agonists, i.e. CpG oligonucleotides, as costimulators to increase diagnostic sensitivity and specificity of our HBV- specific cytokine release assay. METHODS: Whole blood from 80 healthy individuals (n=51 hepatitis B vaccinated, n=29 unvaccinated) was stimulated with hepatitis B surface antigen (HBsAg) or hepatitis B core antigen (HBcAg) in presence or absence of CpG oligonucleotides...
July 21, 2017: Journal of Virological Methods
https://www.readbyqxmd.com/read/28734965/enhanced-immunostimulatory-activity-of-in-silico-discovered-agonists-of-toll-like-receptor-2-tlr2
#11
M S Murgueitio, S Ebner, P Hörtnagl, C Rakers, R Bruckner, P Henneke, G Wolber, S Santos-Sierra
BACKGROUND: Emergent therapies in anticancer vaccination use Toll-like receptors (TLRs) agonists as dendritic cell (DC) vaccine adjuvants. DCs from the patient are isolated, stimulated with TLR agonists and tumor antigens ex vivo and then infused back into the patient. Although some TLR ligands have been tested in clinical trials, novel TLR agonists with improved immunomodulatory properties are essential to optimize treatment success. We report on the discovery of small-molecule TLR2 agonists, with favorable properties as synthetic adjuvants...
July 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28729359/the-%C3%AE-defensin-retrocyclin-101-inhibits-tlr4-and-tlr2-dependent-signaling-and-protects-mice-against-influenza-infection
#12
Daniel Prantner, Kari Ann Shirey, Wendy Lai, Wuyuan Lu, Alexander M Cole, Stefanie N Vogel, Alfredo Garzino-Demo
Despite widespread use of annual influenza vaccines, seasonal influenza-associated deaths number in the thousands each year, in part because of exacerbating bacterial superinfections. Therefore, discovering additional therapeutic options would be a valuable aid to public health. Recently, TLR4 inhibition has emerged as a possible mechanism for protection against influenza-associated lethality and acute lung injury. Based on recent data showing that rhesus macaque θ-defensins could inhibit TLR4-dependent gene expression, we tested the hypothesis that a novel θ-defensin, retrocyclin (RC)-101, could disrupt TLR4-dependent signaling and protect against viral infection...
July 20, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28724768/synthetic-tlr4-and-tlr7-ligands-work-additively-via-myd88-to-induce-protective-antiviral-immunity-in-mice
#13
Peter H Goff, Tomoko Hayashi, Wenqian He, Shiyin Yao, Howard B Cottam, Gene S Tan, Brian Crain, Florian Krammer, Karen Messer, Minya Pu, Dennis A Carson, Peter Palese, Maripat Corr
We have previously demonstrated that the combination of synthetic small molecule Toll-like receptor 4 (TLR4) and TLR7 ligands is a potent adjuvant for recombinant influenza virus hemagglutinin, inducing rapid and sustained immunity protective against influenza viruses in homologous, heterologous and heterosubtypic murine challenge models. Combining TLR4 and TLR7 ligands balances Th1/Th2-type immune responses for long-lived cellular and neutralizing humoral immunity against the viral hemagglutinin. Here, we demonstrate that the protective response induced in mice by this combined adjuvant is dependent upon TLR4 and TLR7 signaling via myeloid differentiation primary response gene 88 (MyD88), indicating that the adjuvants function in vivo via their known receptors with negligible off-target effects to induce protective immunity...
July 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28723271/development-of-three-orthogonal-assays-suitable-for-the-identification-and-qualification-of-pikfyve-inhibitors
#14
Kylie Fogarty, Mohammed Kashem, Andras Bauer, Alexandra Bernardino, Debra Brennan, Brian Cook, Neil Farrow, Teresa Molinaro, Richard Nelson
FYVE-type zinc finger-containing phosphoinositide kinase (PIKfyve) catalyzes the formation of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) from phosphatidylinositol 3-phosphate (PI(3)P). PIKfyve has been implicated in multiple cellular processes, and its role in the regulation of toll-like receptor (TLR) pathways and the production of proinflammatory cytokines has sparked interest in developing small-molecule PIKfyve inhibitors as potential therapeutics to treat autoimmune and inflammatory diseases. We developed three orthogonal assays to identify and qualify small-molecule inhibitors of PIKfyve: (1) a purified component microfluidic enzyme assay that measures the conversion of fluorescently labeled PI(3)P to PI(3,5)P2 by purified recombinant full-length human 6His-PIKfyve (rPIKfyve); (2) an intracellular protein stabilization assay using the kinase domain of PIKfyve expressed in HEK293 cells; and (3) a cell-based functional assay that measures the production of interleukin (IL)-12p70 in human peripheral blood mononuclear cells stimulated with TLR agonists lipopolysaccharide and R848...
July 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28716464/modulating-effects-of-omega-3-fatty-acids-and-pioglitazone-combination-on-insulin-resistance-through-toll-like-receptor-4-in-type-2-diabetes-mellitus
#15
Salma M Eraky, Noha Abdel-Rahman, Laila A Eissa
Toll-like receptor 4 (TLR-4) plays important roles in innate immunity. Changes in the reduction-oxidation balance of tissues can lead to a pro-inflammatory state and insulin resistance. An action thought to be mediated by TLRs. Omega-3 fatty acids and Peroxisome Proliferator Activated Receptor gamma (PPAR-γ) agonists as pioglitazone are used for decreasing inflammation. The aim of this study is to investigate the anti-diabetic effects of combining omega -3 fatty acid with pioglitazone on type 2 diabetes, and the modifying effects on TLR-4...
June 17, 2017: Prostaglandins, Leukotrienes, and Essential Fatty Acids
https://www.readbyqxmd.com/read/28711717/phosphatidylinositol-4-phosphate-5-kinase-%C3%AE-contributes-to-toll-like-receptor-2-mediated-immune-responses-in-microglial-cells-stimulated-with-lipoteichoic-acid
#16
Tu Thi Ngoc Nguyen, Eunjeong Seo, Juyong Choi, Oanh Thi Tu Le, Ji Yun Kim, Ilo Jou, Sang Yoon Lee
Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important lipid regulator of membrane signaling and remodeling processes. Accumulating evidence indicates a link between PIP2 metabolism and Toll-like receptor (TLR) signaling, a key transducer of immune responses such as inflammation, phagocytosis, and autophagy. Microglia are immune effector cells that serve as macrophages in the brain. Here, we examined the potential role of phosphatidylinositol 4-phosphate 5-kinase α (PIP5Kα), a PIP2-producing enzyme, in TLR2 signaling in microglial cells...
July 13, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28703784/targeting-pattern-recognition-receptors-prr-for-vaccine-adjuvantation-from-synthetic-prr-agonists-to-the-potential-of-defective-interfering-particles-of-viruses
#17
REVIEW
Andri Vasou, Nazife Sultanoglu, Stephen Goodbourn, Richard E Randall, Leondios G Kostrikis
Modern vaccinology has increasingly focused on non-living vaccines, which are more stable than live-attenuated vaccines but often show limited immunogenicity. Immunostimulatory substances, known as adjuvants, are traditionally used to increase the magnitude of protective adaptive immunity in response to a pathogen-associated antigen. Recently developed adjuvants often include substances that stimulate pattern recognition receptors (PRRs), essential components of innate immunity required for the activation of antigen-presenting cells (APCs), which serve as a bridge between innate and adaptive immunity...
July 13, 2017: Viruses
https://www.readbyqxmd.com/read/28694807/brucella-omp25-upregulates-mir-155-mir-21-5p-and-mir-23b-to-inhibit-interleukin-12-production-via-modulation-of-programmed-death-1-signaling-in-human-monocyte-macrophages
#18
Beibei Cui, Wenli Liu, Xiaoya Wang, Yu Chen, Qian Du, Xiaomin Zhao, Hai Zhang, Shan-Lu Liu, Dewen Tong, Yong Huang
Brucella spp. infection results in compromised Type1 (Th1) cellular immune response. Several reports have described an immunomodulatory function for Brucella major outer membrane protein Omp25. However, the mechanism by which Omp25 modulates macrophage dysfunction has not been defined. Herein, we reported that Omp25-deficient mutant of Brucella suis exhibited an enhanced ability to induce interleukin (IL)-12 whereas ectopic expression of Omp25 protein inhibited TLR agonists-induced IL-12 p70 production through suppression of both IL-12 p40 and p35 subunit expression in THP-1 cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28686285/toward-a-structural-understanding-of-nucleic-acid-sensing-toll-like-receptors-in-the-innate-immune-system
#19
REVIEW
Zhikuan Zhang, Umeharu Ohto, Toshiyuki Shimizu
The history of mankind has been plagued by the tug of war with viral infections. Toll-like receptors (TLRs) and other receptors of the innate immune system constitute an early defense system against invading viruses by recognizing the viral genetic material, the nucleic acids (NAs). Agonistic ligands of NA-sensing TLRs play an emerging role in the treatment of viral diseases, demonstrating a crucial role of these receptors. Recently, crystal structures have afforded new insights into TLR recognition of NAs...
July 7, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28662082/combination-of-poly-i-c-and-pam3csk4-enhances-activation-of-b-cells-in-vitro-and-boosts-antibody-responses-to-protein-vaccines-in-vivo
#20
Genevieve M Weir, Mohan Karkada, David Hoskin, Marianne M Stanford, Lisa MacDonald, Marc Mansour, Robert S Liwski
Vaccines that can rapidly induce strong and robust antibody-mediated immunity could improve protection from certain infectious diseases for which current vaccine formulations are inefficient. For indications such as anthrax and influenza, antibody production in vivo is a correlate of efficacy. Toll-like receptor (TLR) agonists are frequently studied for their role as vaccine adjuvants, largely because of their ability to enhance initiation of immune responses to antigens by activating dendritic cells. However, TLRs are also expressed on B cells and may contribute to effective B cell activation and promote differentiation into antigen-specific antibody producing plasma cells in vivo...
2017: PloS One
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