Search results for: host immune response

Authors: Ranjeeta Kumari, Makesh M, Gayatri Tripathi, K V Rajendran, Megha Bedekar

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A comparative study on DNA immunization with recombinant glyceraldehyde-3-phosphate dehydrogenase (GAPDH) construct of Edwardsiella tarda (pGPD group) and a bicistronic construct expressing GAPDH plus IFN-γ of Labeo rohita as adjuvant (pGPD+IFN group) was undertaken in Labeo rohita along with the control animals. Successful co-expression of two genes that is GAPDH and IFN-γ was confirmed in SSN-1 cells line by RT-qPCR and western blot. The protective immune response of host to DNA vaccine construct was determined by RPS and specific antibody production. Fishes immunized with plasmids via intramuscular injection (I/M) exhibited a considerable relative percentage survivability of 66.66% in pGPD+IFN immunized group and 53.34% in pGPD immunized group after challenge with E. tarda. Antibody response was also significantly high in pGPD+IFN group at all time points under study. This was analysed by competitive ELISA, using anti GAPDH monoclonal antibodies. The experiment revealed that the GAPDH gene of E. tarda is one of the ideal candidates for generating protective immune response in L. rohita. Further addition of Interferon gamma to DNA vaccine construct can enhance the immune response in host.

Keywords: DNA vaccine, Edwardsiella tarda, Labeo rohita, zoonosis, immune response

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Authors: Gina Leisching, Ray-Dean Pietersen, Carel Van Heerden, Paul Van Helden, Ian Wiid, Bienyameen Baker

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The distinguishing factors that characterize the host response to infection with virulent Mycobacterium tuberculosis (M.tb) are largely confounding. We present an infection study with two genetically closely related M.tb strains that have vastly different pathogenic characteristics. The early host response to infection with these detergent-free cultured strains was analyzed through RNAseq in an attempt to provide information on the subtleties which may ultimately contribute to the virulent phenotype. Murine bone marrow-derived macrophages (BMDMs) were infected with either a hyper- (R5527) or hypovirulent (R1507) Beijing M. tuberculosis clinical isolate. RNAseq revealed 69 differentially expressed host genes in BMDMs during comparison of these two transcriptomes. Pathway analysis revealed activation of the stress-induced and growth inhibitory Gadd45 signaling pathway in hypervirulent infected BMDMs. Upstream regulators of interferon activation such as and IRF3 and IRF7 were predicted to be upregulated in hypovirulent-infected BMDMs. Additional analysis of the host immune response through ELISA and qPCR included the use of human THP-1 macrophages where a robust proinflammatory response was observed after infection with the hypervirulent strain. RNAseq revealed two early-response genes (IER3 and SAA3) and two host-defence genes (OASL1 and SLPI) that were significantly upregulated by the hypervirulent strain. The role of these genes under M.tb infection conditions are largely unknown but here we provide validation of their presence with use of qPCR and Western blot. Further analysis into their biological role under infection with virulent M.tb is required.

Keywords: host-response, Mycobacterium tuberculosis, RNAseq, virulence

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Authors: Saha Saradindu, Das Payel, Somdeb BoseDasgupta

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Tuberculosis caused by Mycobacteria tuberculosis is a dreadful disease and more so with the advent of extreme and total drug-resistant species. Mycobacterial pathogenesis is an ever-changing paradigm from phagosome maturation block to phagosomal escape into macrophage cytosol and finally acid tolerance and survival inside the lysosome. Mycobacteria are adept at subverting the host immune response by highjacking host cell signaling and secreting virulence factors. One such virulence factor is a ser/thr kinase; Protein kinase G (PknG), which is known to prevent phagosome maturation. The host substrates of PknG, allowing successful pathogenesis still remain an enigma. Hence we carried out a comparative phosphoproteomic screen and identified a number of substrates phosphorylated by PknG. We characterized some of these substrates in vivo and in vitro and observed that PknG mediated phosphorylation of these substrates leads to reduced TNFa production as well as decreased response to TNFa induced macrophage necroptosis, thus enabling mycobacterial survival and proliferation.

Keywords: mycobacteria, Protein kinase G, phosphoproteomics, necroptosis

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Authors: Dagmara A. Niedziela, Mark P. Murphy, Orla M. Keane, Finola C. Leonard

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Staphylococcus aureus is the most frequent cause of clinical and subclinical bovine mastitis in Ireland. Mastitis caused by S. aureus is often chronic and tends to recur after antibiotic treatment. This may be due to several virulence factors, including attributes that enable the bacterium to internalize into bovine mammary epithelial cells, where it may evade antibiotic treatment, or evade the host immune response. Four bovine-adapted lineages (CC71, CC97, CC151 and ST136) were identified among a collection of Irish S. aureus mastitis isolates. Genotypic variation of mastitis-causing strains may contribute to different presentations of the disease, including differences in milk somatic cell count (SCC), the main method of mastitis detection. The objective of this study was to investigate the influence of bacterial strain and lineage on host immune response, by employing cell culture methods in vitro as well as an in vivo infection model. Twelve bovine adapted S. aureus strains were examined for internalization into bovine mammary epithelial cells (bMEC) and their ability to induce an immune response from bMEC (using qPCR and ELISA). In vitro studies found differences in a variety of virulence traits between the lineages. Strains from lineages CC97 and CC71 internalized more efficiently into bovine mammary epithelial cells (bMEC) than CC151 and ST136. CC97 strains also induced immune genes in bMEC more strongly than strains from the other 3 lineages. One strain each of CC151 and CC97 that differed in their ability to cause an immune response in bMEC were selected on the basis of the above in vitro experiments. Fourteen first-lactation Holstein-Friesian cows were purchased from 2 farms on the basis of low SCC (less than 50 000 cells/ml) and infection free status. Seven cows were infected with 1.73 x 102 c.f.u. of the CC97 strain (Group 1) and another seven with 5.83 x 102 c.f.u. of the CC151 strain (Group 2). The contralateral quarter of each cow was inoculated with PBS (vehicle). Clinical signs of infection (temperature, milk and udder appearance, milk yield) were monitored for 30 days. Blood and milk samples were taken to determine bacterial counts in milk, SCC, white blood cell populations and cytokines. Differences in disease presentation in vivo between groups were observed, with two animals from Group 2 developing clinical mastitis and requiring antibiotic treatment, while one animal from Group 1 did not develop an infection for the duration of the study. Fever (temperature > 39.5⁰C) was observed in 3 animals from Group 2 and in none from Group 1. Significant differences in SCC and bacterial load between groups were observed in the initial stages of infection (week 1). Data is also being collected on cytokines and chemokines secreted during the course of infection. The results of this study suggest that a strain from lineage CC151 may cause more severe clinical mastitis, while a strain from lineage CC97 may cause mild, subclinical mastitis. Diversity between strains of S. aureus may therefore influence the clinical presentation of mastitis, which in turn may influence disease detection and treatment needs.

Keywords: Bovine mastitis, host immune response, host-pathogen interactions, Staphylococcus aureus

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Authors: Seyyed Mohammad Amin Mousavi Sagharchi, Elham Javanroudi

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Introduction: Tuberculosis (TB) is a known disease with hidden features caused by Mycobacterium tuberculosis (MTB). This disease, which is one of the 10 deadliest in the world, has caused millions of deaths in recent decades. Furthermore, TB is responsible for infecting about 30% population of world. Like any infection, TB can activate the immune system by locating and colonization in the human body, especially in the alveoli. TB is granulomatosis, so MTB can absorb the host’s immune cells and other cells to form granuloma. Method: Different databases (e.g., PubMed) were recruited to prepare this paper and fulfill our goals to search and find effective papers and investigations. Results: Immune response to MTB is related to T cell killers and contains CD1, CD4, and CD8 T lymphocytes. CD1 lymphocytes can recognize glycolipids, which highly exist in the Mycobacterial fatty cell wall. CD4 lymphocytes and macrophages form granuloma, and it is the main line of immune response to Mycobacteria. On the other hand, CD8 cells have cytolytic function for directly killing MTB by secretion of granulysin. Other functions and secretion to the deal are interleukin-12 (IL-12) by induction of expression interferon-γ (INF-γ) for macrophages activation and creating a granuloma, and tumor necrosis factor (TNF) by promoting macrophage phagolysosomal fusion. Conclusion: Immune cells in battle with MTB are macrophages, dendritic cells (DCs), neutrophils, and natural killer (NK) cells. These immune cells can recognize the Mycobacterium by various receptors, including Toll-like receptors (TLRs), Nod-like receptors (NLRs), and C-type lectin receptors (CLRs) located in the cell surface. In human alveoli exist about 50 dendritic macrophages, which have close communication with other immune cells in the circulating system and epithelial cells to deal with Mycobacteria. Against immune cells, MTB handles some factors (e.g., cordfactor, O-Ag, lipoarabinomannan, sulfatides, and adenylate cyclase) and practical functions (e.g., inhibition of macrophages).

Keywords: mycobacterium tuberculosis, immune responses, immunological mechanisms, respiratory tuberculosis

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Authors: K. Żak, S. Przetocka, R. Kitel, K. Guzik, B. Musielak, S. Malicki, G. Dubin, T. A. Holak

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Studies on tumor genesis revealed a number of factors that may potentially serve as molecular targets for immunotherapies. One of such promising targets are PD1 and PDL1 proteins. PD1 (Programmed cell death protein 1) is expressed by activated T cells and plays a critical role in modulation of the host's immune response. One of the PD1 ligands -PDL1- is expressed by macrophages, monocytes and cancer cells which exploit it to avoid immune attack. The notion of the mechanisms used by cancer cells to block the immune system response was utilized in the development of therapies blocking PD1-PDL1 interaction. Up to date, human PD1-PDL1 complex has not been crystallized and structure of the mouse-human complex does not provide a complete view of the molecular basis of PD1-PDL1 interactions. The purpose of this study is to obtain crystal structure of the human PD1-PDL1 complex which shall allow rational design of small molecule inhibitors of the interaction. In addition, the study presents results of binding small-molecules to PD1 and fragment docking towards PD1 protein which will facilitate the design and development of small–molecule inhibitors of PD1-PDL1 interaction.

Keywords: PD1, PDL1, cancer, small molecule, drug discovery

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Authors: H. Al-Khalifa, A. Al-Nasser

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The main immune organs in poultry are the thymus, spleen and bursa of Fabricius. During an immune response, mature lymphocytes and other immune cells interact with antigens in these tissues. Consequently, the mass of these organs can in some cases indicate immune status. The objective of the current study was to investigate the effect of feeding flaxseed on immune tissue weights. Cobb 500 broiler chickens were fed flaxseed at 15%, the control diet did not contain any flaxseed. Results showed that dietary supplementation with flaxseed did not affect the weights of the spleens of broiler chickens. However, it significantly lowered bursa weights (p<0.01), compared to the control diet. In addition, the bursae were thinner in appearance compared with bursii from chickens fed the control diets.

Keywords: bursa of fabricius, flaxseed, spleen, thymus

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Authors: Michelle Maurer, Antonia Last, Mark S. Gresnigt, Bernhard Hube, Alexander S. Mosig

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The intestinal epithelium forms an essential barrier to prevent translocation of microorganisms, toxins or other potentially harmful molecules into the bloodstream. In particular, dendritic cells of the intestinal epithelium orchestrate an adapted response of immune tolerance to commensals and immune defense against invading pathogens. Systemic inflammation is typically associated with a dysregulation of this adapted immune response and is accompanied by a disruption of the epithelial and endothelial gut barrier which enables dissemination of pathogens within the human body. To understand the pathophysiological mechanisms underlying the inflammation-associated gut barrier breakdown, it is crucial to elucidate the complex interplay of the host and the intestinal microbiome. A microfluidically perfused three-dimensional intestine-on-chip model was established to emulate these processes in the presence of immune cells, commensal bacteria, and facultative pathogens. Multi-organ tissue flow (MOTiF) biochips made from polystyrene were used for microfluidic perfusion of the intestinal tissue model. The biochips are composed of two chambers separated by a microporous membrane. Each chamber is connected to inlet and outlet channels allowing independent perfusion of the individual channels and application of microfluidic shear stress. Human umbilical vein endothelial cells (HUVECs), monocyte-derived macrophages and intestinal epithelial cells (Caco-2) were assembled on the biochip membrane. Following 7 – 14 days of growth in the presence of physiological flow conditions, the epithelium was colonized with the commensal bacterium Lactobacillus rhamnosus, while the endothelium was perfused with peripheral blood mononuclear cells (PBMCs). Additionally, L. rhamnosus was co-cultivated with the opportunistic fungal pathogen Candida albicans. Within one week of perfusion, the epithelial cells formed self-organized and well-polarized villus- and crypt-like structures that resemble essential morphological characteristics of the human intestine. Dendritic cells were differentiated in the epithelial tissue that specifically responds to bacterial lipopolysaccharide (LPS) challenge. LPS is well-tolerated at the luminal epithelial side of the intestinal model without signs of tissue damage or induction of an inflammatory response, even in the presence of circulating PBMC at the endothelial lining. In contrast, LPS stimulation at the endothelial side of the intestinal model triggered the release of pro-inflammatory cytokines such as TNF, IL-1β, IL-6, and IL-8 via activation of macrophages residing in the endothelium. Perfusion of the endothelium with PBMCs led to an enhanced cytokine release. L. rhamnosus colonization of the model was tolerated in the immune competent tissue model and was demonstrated to reduce damage induced by C. albicans infection. A microfluidic intestine-on-chip model was developed to mimic a systemic infection with a dysregulated immune response under physiological conditions. The model facilitates the colonization of commensal bacteria and co-cultivation with facultative pathogenic microorganisms. Both, commensal bacteria alone and facultative pathogens controlled by commensals, are tolerated by the host and contribute to cell signaling. The human intestine-on-chip model represents a promising tool to mimic microphysiological conditions of the human intestine and paves the way for more detailed in vitro studies of host-microbiota interactions under physiologically relevant conditions.

Keywords: host-microbiota interaction, immune tolerance, microfluidics, organ-on-chip

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Authors: Iñaki Iturria, Pasquale Russo, Montserrat Nacher-Vázquez, Giuseppe Spano, Paloma López, Miguel Angel Pardo

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Introduction: It is known that some Lactic Acid Bacteria (LAB) present an interesting probiotic effect. Probiotic bacteria stimulate host resistance to microbial pathogens and thereby aid in immune response, and modulate the host's immune responses to antigens with a potential to down-regulate hypersensitivity reactions. Therefore, probiotic therapy is valuable against intestinal infections and may be beneficial in the treatment of Inflammatory Bowel Disease (IBD). Several in vitro tests are available to evaluate the probiotic potential of a LAB strain. However, an in vivo model is required to understand the interaction between the host immune system and the bacteria. During the last few years, zebrafish (Danio rerio) has gained interest as a promising vertebrate model in this field. This organism has been extensively used to study the interaction between the host and the microbiota, as well as the host immune response under several microbial infections. In this work, we report on the use of the zebrafish model to investigate in vivo the colonizing ability and the immunomodulatory effect of probiotic LAB. Methods: Lactobacillus strains belonging to different LAB species were fluorescently tagged and used to colonize germ-free zebrafish larvae gastrointestinal tract (GIT). Some of the strains had a well-documented probiotic effect (L. acidophilus LA5); while others presented an exopolysaccharide (EPS) producing phenotype, thus allowing evaluating the influence of EPS in the colonization and immunomodulatory effect. Bacteria colonization was monitored for 72 h by direct observation in real time using fluorescent microscopy. CFU count per larva was also evaluated at different times. The immunomodulatory effect was assessed analysing the differential expression of several innate immune system genes (MyD88, NF-κB, Tlr4, Il1β and Il10) by qRT- PCR. The anti-inflammatory effect was evaluated using a chemical enterocolitis zebrafish model. The protective effect against a pathogen was also studied. To that end, a challenge test was developed using a fluorescently tagged pathogen (Vibrio anguillarum-GFP+). The progression of the infection was monitored up to 3 days using a fluorescent stereomicroscope. Mortality rates and CFU counts were also registered. Results and conclusions: Larvae exposed to EPS-producing bacteria showed a higher fluorescence and CFU count than those colonized with no-EPS phenotype LAB. In the same way, qRT-PCR results revealed an immunomodulatory effect on the host after the administration of the strains with probiotic activity. A downregulation of proinflammatory cytoquines as well as other cellular mediators of inflammation was observed. The anti-inflammatory effect was found to be particularly marked following exposure to LA% strain, as well as EPS producing strains. Furthermore, the challenge test revealed a protective effect of probiotic administration. As a matter of fact, larvae fed with probiotics showed a decrease in the mortality rate ranging from 20 to 35%. Discussion: In this work, we developed a promising model, based on the use of gnotobiotic zebrafish coupled with a bacterial fluorescent tagging in order to evaluate the probiotic potential of different LAB strains. We have successfully used this system to monitor in real time the colonization and persistence of exogenous LAB within the gut of zebrafish larvae, to evaluate their immunomodulatory effect and for in vivo competition assays. This approach could bring further insights into the complex microbial-host interactions at intestinal level.

Keywords: gnotobiotic, immune system, lactic acid bacteria, probiotics, zebrafish

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Authors: Husham Bayazed

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Purpose of Presentation: The eye is one of a few sites in the body with immune privilege (IP). However, this IP is relatively easily bypassed in the face of sufficient strong local or systemic immunological responses. As immune responses are crucial elements of the repair response, the eye has developed distinct mechanisms to deliver immune responses to injury in the avascular regions of the eye. This presentation may cover and provide an overview of the mechanisms that dictate immune cell trafficking to the local ocular microenvironment in response to different autoimmune and inflammatory-mediated diseases. Recent Findings: Literature reviews declare that immune responses and inflammation play a key role in a diverse range of eye diseases. In recent years, our understanding of ocular immune responses has widely spread in ocular surface inflammation, uveitis, age-related macular degeneration (AMD), glaucoma, transplantation rejection, and other ocular diseases. It is becoming increasingly clear that multiple seemingly unrelated diseases involve immune responses with common themes in their ocular pathogenesis. Recent studies are focusing on elucidating the pathogenesis of ocular inflammatory disease to identify new targets for immunotherapy that will not only improve efficacy but also minimize adverse effects from traditional therapy. Summary: While IP was believed to protect the eye from day-to-day inflammatory insults, however, it is relatively easily breached in the face of different strong local or systemic immunological and inflammatory responses. Therefore, the ocular immune response encapsulates the full range of classical and non-classical immune responses and demonstrates many features which are reflected in other tissues, but eye tissues, by modifying these responses, may reveal unexpected and novel findings which are relevant to immune responses generally. This may have therapeutic potential for new targeting immunotherapy, restoring immune tolerance in ocular autoimmune and inflammatory diseases, and preventing rejection such as stem cells, currently being considered for treatment of worldwide blinding diseases such as AMD.

Keywords: ocular diseases, immunology, immune privilege, immunotherapy

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Authors: Florian Billing, Soren Segan, Meike Jakobi, Elsa Arefaine, Aliki Jerch, Xin Xiong, Matthias Becker, Thomas Joos, Burkhard Schlosshauer, Ulrich Rothbauer, Nicole Schneiderhan-Marra, Hanna Hartmann, Christopher Shipp

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The immune response plays a major role in implant biocompatibility, but an understanding of how to design biomaterials for specific immune responses is yet to be achieved. We aimed to better understand how changing certain material properties can drive immune responses. To this end, we tested immune response to experimental implant coatings that vary in specific characteristics. A layer-by-layer approach was employed to vary surface charge and wettability. Human-based in vitro models (THP-1 macrophages and primary peripheral blood mononuclear cells (PBMCS)) were used to assess immune responses using multiplex cytokine analysis, flow cytometry (CD molecule expression) and microscopy (cell morphology). We observed dramatic differences in immune response due to specific alterations in coating properties. For example altering the surface charge of coating A from anionic to cationic resulted in the substantial elevation of the pro-inflammatory molecules IL-1beta, IL-6, TNF-alpha and MIP-1beta, while the pro-wound healing factor VEGF was significantly down-regulated. We also observed changes in cell surface marker expression in relation to altered coating properties, such as CD16 on NK Cells and HLA-DR on monocytes. We furthermore observed changes in the morphology of THP-1 macrophages following cultivation on different coatings. A correlation between these morphological changes and the cytokine expression profile is ongoing. Targeted changes in biomaterial properties can produce vast differences in immune response. The properties of the coatings examined here may, therefore, be a method to direct specific biological responses in order to improve implant biocompatibility.

Keywords: biomaterials, coatings, immune system, implants

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Authors: J. B. Minari, O. B. Oloyede

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Polymorphonuclear neutrophils (PMNs) play a crucial role in a variety of infections caused by bacteria, fungi, and parasites. Indeed, the involvement of PMNs in host defence against Plasmodium falciparum is well documented both in vitro and in vivo. Many of the antimalarial drugs such as chloroquine used in the treatment of human malaria significantly reduce the immune response of the host in vitro and in vivo. Myeloperoxidase is the most abundant enzyme found in the polymorphonuclear neutrophil which plays a crucial role in its function. This study was carried out to investigate the effect of chloroquine on the enzyme. In investigating the effects of the drug on myeloperoxidase, the influence of concentration, pH, partition ratio estimation and kinetics of inhibition were studied. This study showed that chloroquine is concentration-dependent inhibitor of myeloperoxidase with an IC50 of 0.03 mM. Partition ratio estimation showed that 40 enzymatic turnover cycles are required for complete inhibition of myeloperoxidase in the presence of chloroquine. The influence of pH on the effect of chloroquine on the enzyme showed significant inhibition of myeloperoxidase at physiological pH. The kinetic inhibition studies showed that chloroquine caused a non-competitive inhibition with an inhibition constant Ki of 0.27mM. The results obtained from this study shows that chloroquine is a potent inhibitor of myeloperoxidase and it is capable of inactivating the enzyme. It is therefore considered that the inhibition of myeloperoxidase in the presence of chloroquine as revealed in this study may partly explain the impairment of polymorphonuclear neutrophil and consequent immunosuppression of the host defence system against secondary infections.

Keywords: myeloperoxidase, chloroquine, inhibition, neutrophil, immune

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Authors: Li Li, Li-Ru Xia, He-Ye Wang, Xiao-Dong Bi

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In this paper, we presented a highly sensitive immune-affinity monolithic array for detection of α-fetoprotein (AFP) and carcinoembryonic antigen (CEA). Firstly, the epoxy functionalized monolith arrays were fabricated using UV initiated copolymerization method. Scanning electron microscopy (SEM) image showed that the poly(BABEA-co-GMA) monolith exhibited a well-controlled skeletal and well-distributed porous structure. Then, AFP and CEA immune-affinity monolithic arrays were prepared by immobilization of AFP and CEA antibodies on epoxy functionalized monolith arrays. With a non-competitive immune response format, the presented AFP and CEA immune-affinity arrays were demonstrated as an inexpensive, flexible, homogeneous and stable array for detection of AFP and CEA.

Keywords: chemiluminescent detection, immune-affinity, monolithic copolymer array, UV-initiated copolymerization

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Authors: Husham Bayazed

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Purpose of presentation: Pregnancy represents the most important period for the conservation of the species. The immune system is one of the most important systems protecting the mother against the environment and preventing damage to the fetus. This presentation aims to review and discuss the role of the immune system during pregnancy, the evolutionary inflammatory process through pregnancy, infectious and environmental exposure influences on the mother and the fetus, and the impacts of sexual dimorphism of the placenta on offspring susceptibility to different disorders. Recent Findings: In 1960, Peter Medawar (Nobel Prize Winner) proposed that the fetus, a semi-allograft, is similar to a tissue graft that escapes rejection through a mechanism involving systemic immune suppression (Graft –Host response). However, recent researchers and studies have documented that implantation means inflammation, and the inflammatory process is considered a breach of tolerance in pregnancy with immune induction, which is necessary for the protection of the mother and the fetus against infections and environmental triggers. This inflammatory process should be maintained during different pregnancy phases till parturition, and any block at any phase will be associated with pregnancy complications, including pregnancy failure or loss, miscarriage, and preterm birth subsequently. Maternal immune activation following any trigger can have a positive effect on the fetus. The old concept of the placenta being asexual is inaccurate, and being with sexual dimorphism with clear differences in susceptibility to different factors that stimulate maternal immunity. Summary: The presence of different immune cells ((i.e., T cells, B cells, NK cells, etc.) at the implantation site is considered proof of a strong maternal immune response to the fetus. Therefore, human pregnancy is considered a unique immunological paradigm requiring maternal immune modulation rather than suppression. So Medawar's postulation of maternal systemic immunosuppression is wrong. Maternal immune system activation triggered by infections, stress, diet, and pollution can have a positive effect on the fetus, with the development of fetal-trained immunity necessary for survival. The sexual dimorphism of the placenta seems to have an impact on the differences in sex susceptible to the environment maternal risk stimuli. This link to why the incidence of autism is increasing more among boys than girls.

Keywords: pregnancy, maternal immunity, implantation and inflammation, placenta sexual dimorphism

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Authors: Lea Boidin, Martha Baydoun, Bertrand Leroux, Olivier Morales, Samir Acherar, Celine Frochot, Nadira Delhem

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Ovarian cancer (OC) is one of the most defying diseases in gynecologic oncology. Even though surgery remains crucial in the therapy of patients with primary ovarian cancer, recurrent recidivism calls for the development of new therapy protocols to propose for patients dealing with this cancer. FRα is described as a tumor‐associated antigen in OC, where FRα expression is usually linked with more poorly differentiated, aggressive tumors. The Photodynamic treatment (PDT) available data have shown improvements in the uptake of small tumors and in the induction of a proper anti-tumoral immune response. In order to target specifically peritoneal metastatis, which overexpress FRα, a new-patented PS coupled with folic acid has been developed in our team. Herein we propose PDT using this new patented PS for PDT applied in an in vivo mice model. The efficacy of the treatment was evaluated in mice without and with PBMC reconstitution. Mice were divided into four groups: Non-Treated, PS, Light Only, and PDT Treated and subjected to illumination by laser set at 668nm with a duration of illumination of 45 minutes (or 1 min of illumination followed by 2 minutes of pause repeated 45 times). When mice were not reconstituted and after fractionized PDT protocol, a significant decrease in the tumor volume was noticed. An induction in the anti-tumoral cytokine IFNγ chaperoned this decrease while a subsequent inhibition in the cytokine TGFβ. Even more crucial, when mice were reconstituted and upon PDT, the fold of tumor decrease was even higher. An immune response was activated decoded with an increase in NK, CD3 +, LT helper and Cytotoxic T cells. Thereafter, an increase in the expression of the cytokines IFNγ and TNFα were noticed while an inhibition in TGFβ, IL8 and IL10 accompanied this immune response activation. Therefore, our work has shown for the first time that a fractionized PDT protocol using a folate-targeted PDT is effective for treatment of ovarian cancer. The interest in using PDT in this case, goes beyond the local induction of tumor apoptosis only, but can promote subsequent anti-tumor response. Most of the therapies currently used to treat ovarian cancer, have an uncooperative outcomes on the host immune response. The readiness of a tumor adjuvant treatment like PDT adequate in eliminating the tumor and in concert stimulating anti-tumor immunity would be weighty.

Keywords: folate receptor, ovarian cancer, photodynamic therapy, humanized mice model

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Authors: Aruha Khan, Brynn E. Kankel, Paraskevi Papadopoulou

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In recent years, extensive research upon ‘stress’ has provided insight into its two distinct guises, namely the short–term (fight–or–flight) response versus the long–term (chronic) response. Specifically, the long–term or chronic response is associated with the suppression or dysregulation of immune function. It is also widely noted that the occurrence of cancer is greatly correlated to the suppression of the immune system. It is thus necessary to explore the impact of long–term or chronic stress upon the prevalence and risk of cancer. To what extent can the dysregulation of immune function caused by long–term exposure to stress be controlled or minimized? This study focuses explicitly upon immunosuppression due to its ability to increase disease susceptibility, including cancer itself. Based upon an analysis of the literature relating to the fundamental structure of the immune system alongside the prospective linkage of chronic stress and the development of cancer, immunosuppression may not necessarily correlate directly to the acquisition of cancer—although it remains a contributing factor. A cross-sectional analysis of the survey data from the University of Tennessee Medical Center (UTMC) and Harvard Medical School (HMS) will provide additional supporting evidence (or otherwise) for the hypothesis of the study about whether immunosuppression (caused by the chronic stress response) notably impacts the prevalence of cancer. Finally, a multidimensional framework related to education on chronic stress and its effects is proposed.

Keywords: immune system, immunosuppression, long–term (chronic) stress, risk of cancer

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Authors: Arash Jafari, Somaye Bahrami, Mohammad Hossein Razi Jalali

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The aim of this study was the isolation and identification of excretory-secretory and somatic antigens from D. dendriticum by SDS-PAGE and evaluation of humeral immune response against these antigens. The sera of infected sheep with different infection degrees were collected. Somatic and ES proteins were isolated with SDS PAGE. Immunogenicity properties of the resulting proteins were determined using western blot analysis. The total extract of somatic antigens analysed by SDS-PAGE revealed 21 proteins. In mild infection, bands of 130 KDa were immune dominant. In moderate infections 48, 80 and 130 KDa and in heavy infections 48, 60, 80, 130 KDa were detected as immune dominant bands. In ES antigens, mild infection 130 KDa, in moderate infection 100, 120 and 130 KDa and in heavy infection 45, 80, 85, 100, 120 and 130 KDa were immune dominant bands. The most immunogenic protein band during different degrees of infection was 130KDa.

Keywords: Dicrocoelium dendriticum excretory-secretory antigens, somatic antigens, western blot

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Authors: Atefeh Esmailnejad, Gholamreza Nikbakht Brujeni

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Major histocompatibility complex (MHC) is one of the best characterized genetic regions associated with immune responses and controlling disease resistance in chicken. Association of the MHC with a wide range of immune responses makes it a valuable predictive factor for the disease pathogenesis and outcome. In this study, the association of MHC with cell-mediated immune responses was analyzed in commercial broiler chicken. The tandem repeat LEI0258 was applied to investigate the MHC polymorphism. Cell-mediated immune response was evaluated by peripheral blood lymphocyte proliferation assay using MTT method. Association study revealed a significant influence of MHC alleles on cellular immune responses in this population. Alleles 385 and 448 bp were associated with elevated cell-mediated immunity. Haplotypes associated with improved immune responses could be considered as candidate markers for disease resistance and applied to breeding strategies.

Keywords: MHC, cell-mediated immunity, broiler, chicken

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Authors: Ahmed Zaghawa

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Rift Valley Fever is an economically specific disease of the health and arboviral disease that affects many types of animals, causing significant economic losses in livestock, and it is transmitted to humans and has public health issues. The vaccine program is the backbone for the control of this disease. The goal of this study was to apply a new approach to evaluate the inactivated RVF vaccine developed in Egypt. In this study, the RVF vaccine was evaluated in young puppies and compared with sheep; the findings showed that young puppies were susceptible to infection with the inhibitory RVF virus and had a strong response of antibodies with two doses of the RVF vaccine within the two-week interval. The neutralization indices began to appear to the protective level on the 7th day at 1.35 and steadily elevated at 14,21 and 28 days to 1.35, 1.43, and 1.20, respectively, in comparison to the control group. While in sheep, the neutralization indices began to appear to the protective level on the 7th day at 1.10 and remain strongly at high titer at 14, 21, and 28 days with NI values 1.20, 1.50, and 1.50, respectively. The new approach for comparing the immune response in puppies and sheep via SNT indicated the high response in both species was evident as well as the neutralization indices values in young puppies at different periods after RVF vaccination reported the value of 1.08±0.03, 1.23±0.04, 1.30±0.03, and 1.45±0.02 after 7, 14, 21, and 28 days post-vaccination respectively. On the other side, a nearly similar immune response was noticed in sheep with NI values of 1.15±0.02, 1.27±0.02, 1.42±0.05, and 1.55±0.03 at 7, 14, 21, and 28 days post-vaccination, respectively. In conclusion, young puppies are similar to sheep in developing antibodies after vaccination with the RVF vaccine and can replace sheep for evaluating the efficacy of the RVF vaccine. Further studies are mandatory to assess more recent methods for evaluating inhibition of the RVF vaccine.

Keywords: immune response, puppies, RVF, sheep, vaccine

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Authors: P. O. Ughachukwu, P. O. Okonkwo, P. C. Unekwe, J. O. Ogamba

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Background: The prevalence of hepatitis B viral infection is high worldwide with liver cirrhosis and hepatocellular carcinoma as important complications. Cases of poor antibody response to hepatitis B vaccination abound. Immunosuppression, especially from glucocorticoids, is often cited as a cause of poor antibody response and there are documented evidences of irrational administration of glucocorticoids to children and adults. The study was, therefore, designed to find out if administration of glucocorticoids affects immune response to vaccination against hepatitis B in mice. Methods: Mice of both sexes were randomly divided into 2 groups. Daily intramuscular methylprednisolone injections, (15 mg kg-1), were given to the test group while sterile deionized water (0.1ml) was given to control mice for 30 days. On day 6 all mice were given 2 μg (0.1ml) hepatitis B vaccine and a booster dose on day 27. On day 34, blood samples were collected and analyzed for anti-HBs titres using enzyme-linked immunosorbent assay (ELISA). Statistical analysis was done using Graph Pad Prism 5.0 and the results taken as statistically significant at p value < 0.05. Results: There were positive serum anti-HBs responses in all mice groups but the differences in titres were not statistically significant. Conclusions: At the dosages and length of exposure used in this study, methylprednisolone injection did not significantly inhibit anti-HBs response in mice following immunization against hepatitis B virus. By extrapolation, methylprednisolone, when used in the usual clinical doses and duration of therapy, is not likely to inhibit immune response to hepatitis B vaccinations in man.

Keywords: anti-HBs, hepatitis B vaccine, immune response, methylprednisolone, mice

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Authors: Wan Liu, Haibo Wang, Cathy Huang, Zhiwu Tan, Zhiwei Chen

Abstract:

The tremendous diversity of HIV-1 has been a major challenge for an effective AIDS vaccine development. Mosaic approach presents the potential for vaccine design aiming for global protection. The mosaic antigen of HIV-1 Gag allows antigenic breadth for vaccine-elicited immune response against a wider spectrum of viral strains. However, the enhancement of immune response using vaccines is dependent on the strategy used. Heterologous prime/boost regimen has been shown to elicit high levels of immune responses. Here, we investigated whether priming using plasmid DNA with electroporation followed by boosting with the live replication-competent modified vaccinia virus vector TianTan (MVTT) combined with the mosaic antigenic sequence could elicit a greater and broader antigen-specific response against HIV-1 Gag in mice. When compared to DNA or MVTT alone, or MVTT/MVTT group, DNA/MVTT group resulted in coincidentally high frequencies of broadly reactive, Gag-specific, polyfunctional, long-lived, and cytotoxic CD8+ T cells and increased anti-Gag antibody titer. Meanwhile, the vaccination could upregulate PD-1+, and Tim-3+ CD8+ T cell, myeloid-derived suppressive cells and Treg cells to balance the stronger immune response induced. Importantly, the prime/boost vaccination could help control the EcoHIV and mesothelioma AB1-gag challenge. The stronger protective Gag-specific immunity induced by a Mosaic DNA/MVTT vaccine corroborate the promise of the mosaic approach, and the potential of two acceptably safe vectors to enhance anti-HIV immunity and cancer prevention.

Keywords: DNA/MVTT vaccine, EcoHIV, mosaic antigen, mesothelioma AB1-gag

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Authors: Mir Mohammad Reza Hosseini

Abstract:

In new years immune checkpoint inhibitors have gathered care as being one of the greatest talented kinds of immunotherapy on the prospect. There has been a specific emphasis on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). In 2011, ipilimumab, the primary antibody obstructive an immune checkpoint (CTLA4) was authorized. It is now documented that recognized tumors have many devices of overpowering the antitumor immune response, counting manufacture of repressive cytokines, staffing of immunosuppressive immune cells, and upregulation of coinhibitory receptors recognized as immune checkpoints. This was fast followed by the growth of monoclonal antibodies directing PD1 (pembrolizumab and nivolumab) and PDL1 (atezolizumab and durvalumab). Anti-PD1/PDL1 antibodies have developed some of the greatest extensively set anticancer therapies. We also compare and difference their present place in cancer therapy and designs of immune-related toxicities and deliberate the role of dual immune checkpoint inhibition and plans for the organization of immune-related opposing proceedings. In this review, the employed code and present growth of numerous immune checkpoint inhibitors are abridged, while the communicating device and new development of Immune checkpoint inhibitors in cancer therapy-based synergistic therapies with additional immunotherapy, chemotherapy, phototherapy, and radiotherapy in important and clinical educations in the historical 5 years are portrayed and tinted. Lastly, we disapprovingly measure these methods and effort to find their fortes and faintness based on pre-clinical and clinical information.

Keywords: checkpoint, cancer therapy, PD-1, PDL-1, CTLA4, immunosuppressive

Procedia PDF Downloads 145

Authors: Hager Elsheikh, Matthias Sendler, Juliana Glaubnitz

Abstract:

In pancreatitis, an inflammatory reaction occurs in the pancreatic secretory cells due to premature activation of proteases, leading to pancreatic self-digestion and necrotic cell death of acinar cells. Acute pancreatitis in patients is characterized by a severe immune reaction that could lead to serious complications, such as organ failure or septic shock, if left untreated. Chronic pancreatitis is a recurrence of episodes of acute pancreatitis resulting in a fibro-inflammatory immune response, in which the type 2 immune response is primarily driven by AAMs in the pancreas. One of the most important signaling pathways for M2 macrophage activation is the IL-4/STAT6 pathway. Pancreatic fibrosis is induced by the hyperactivation of pancreatic stellate cells by dysregulation in the inflammatory response, leading to further damage, autodigestion and possibly necrosis of pancreatic acinar cells. The aim of this research is to investigate the effect of STAT6 knockout in disease severity and development of fibrosis wound healing in the presence of different macrophage populations, regulated by the type 2 immune response, after inducing chronic and/or acute pancreatitis in mice models via cerulean injection. We further investigate the influence of the JAK/STAT6 signaling pathway on the balance of fibrosis and regeneration in STAT6 deficient and wild-type mice. The characterization of resident and recruited macrophages will provide insight into the influence of the JAK/STAT6 signaling pathway on infiltrating cells and, ultimately, tissue fibrosis and disease severity.

Keywords: acute and chronic pancreatitis, tissue regeneration, macrophage polarization, Gastroenterology

Procedia PDF Downloads 45

Authors: N. Choobkar, M. Rezaeimanesh, A. M. Emami Rad, M. Ghaeni, H. Norouzi, S. Pahlavani, M. S. Tamasoki, E. Nezafatian

Abstract:

Antibiotics are used to increase the immune and wound healing in many animals . But due to the residual effects of a drug , researchers sought to replace them with natural materials such as Plant extracts. Falcaria vulgaris is the most attractive sources of the new drugs. Falcaria vulgaris (locally named Ghazzyaghi/Poghazeh) is a member of Umbelliferae family which grows near farmlands and is consumed as a vegetable in some regions of Iran. In the West of the country, in the wound healing and irregularities in the digestive system is also used. There were no scientific reports available in literature in support of the traditional claims of F. vulgaris in fish. The present study is therefore an attempt to assess the efficacy of this indigenous herb for its healing effect in common carp (Cyprinus carpio). Falcaria vulgaris at concentrations of 0, 2 and 10 % with Lophag foods used on wound healing of common carp and immune response, and weight grow and survival during periods of 21 days with feeding 2 times per day on the basis of body weight. The results showed that, compared with the control group, using of concentration 10 % F. vulgaris have significant effect on wound healing and stimulates the immune system by increasing white blood cells (WBC) and weight grow and survival of carp. The herb can used in wound healing, increased resistance to disease and weight grow in fish and the beneficial effects of this combination goes back to man.

Keywords: common carp, falcaria vulgaris, immune response, wound healing

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Authors: Supanan Chansap, Werachon Cheukamud, Pornanan Kueakhai, Narin Changklungmoa

Abstract:

Fasciola species (Fasciola spp.) is caused fasciolosis in ruminants such as cattle, sheep, and buffalo. Fasciola gigantica (F.gigantica) commonly infects tropical regions. Fasciola hepatica (F.hepatica) in temperate regions. Liver fluke infection affects livestock economically, for example, reduced milk and meat production, weight loss, sterile animals. Currently, Triclabendazole is used to treat liver flukes. However, liver flukes have also been found to be resistant to drugs in countries. Therefore, vaccination is an attractive alternative to prevent liver fluke infection. Peptide vaccines are new vaccine technologies that mimic epitope antigens that trigger an immune response. An interesting antigen used in vaccine production is catepsin L, a family of proteins that play an important role in the life of the parasite in the host. This study aims to identify immunogenic regions of protein and construct a multi-epidetope vaccine using an immunoinformatic tool. Fasciola gigantica Cathepsin L1 (FgCatL1), Fasciola gigantica Cathepsin L1G (FgCatL1G), and Fasciola gigantica Cathepsin L1H (FgCatL1H) were predicted B-cell and Helper T lymphocytes (HTL) by Immune Epitope and Analysis Resource (IEDB) servers. Both B-cell and HTL epitopes aligned with cathepsin L of the host and Fasciola hepatica (F. hepatica). Epitope groups were selected from non-conserved regions and overlapping sequences with F. hepatica. All overlapping epitopes were linked with the GPGPG and KK linker. GPGPG linker was linked between B-cell epitope. KK linker was linked between HTL epitope and B-cell and HTL epitope. The antigenic scores of multi-epitope peptide vaccine was 0.7824. multi-epitope peptide vaccine was non-allergen, non-toxic, and good soluble. Multi-epitope peptide vaccine was predicted tertiary structure and refinement model by I-Tasser and GalaxyRefine server, respectively. The result of refine structure model was good quality that was generated by Ramachandran plot analysis. Discontinuous and linear B-cell epitopes were predicted by ElliPro server. Multi-epitope peptide vaccine model was two and seven of discontinuous and linear B-cell epitopes, respectively. Furthermore, multi-epitope peptide vaccine was docked with Toll-like receptor 2 (TLR-2). The lowest energy ranged from -901.3 kJ/mol. In summary, multi-epitope peptide vaccine was antigenicity and probably immune response. Therefore, multi-epitope peptide vaccine could be used to prevent F. gigantica infections in the future.

Keywords: fasciola gigantica, Immunoinformatic tools, multi-epitope, Vaccine

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Authors: Vaiyapuri Subbarayn Periasamy, Jegan Athinarayanan, Ali A. Alshatwi

Abstract:

The widespread use of Titanium oxide nanoparticles (TiO2-NPs), now are found with different physic-chemical properties (size, shape, chemical properties, agglomeration, etc.) in many processed foods, agricultural chemicals, biomedical products, food packaging and food contact materials, personal care products, and other consumer products used in daily life. Growing evidences have been highlighted that there are risks of physico-chemical properties dependent toxicity with special attention to “TiO2-NPs and human immune system”. Unfortunately, agglomeration and aggregation have frequently been ignored in immuno-toxicological studies, even though agglomeration and aggregation would be expected to affect nanotoxicity since it changes the size, shape, surface area, and other properties of the TiO2-NPs. In this present investigation, we assessed the immune toxic effect of TiO2-NPs on human immune cells Total WBC including Lymphocytes (T cells (CD3+), T helper cells (CD3+, CD4+), Suppressor/cytotoxic T cells (CD3+/CD8+) and NK cells (CD3-/CD16+ and CD56+), Monocytes (CD14+, CD3-) and B lymphocytes (CD19+, CD3-) in order to find the immunological response (IL1A, IL1B, IL2 IL-4, IL5 IL-6, IL-10, IL-12, IL-13, IFN-γ, TGF-β, and TNF-a) and redox gene regulation (TNF, p53, BCl-2, CAT, GSTA4, TNF, CYP1A, POR, SOD1, GSTM3, GPX1, and GSR1)-linking physicochemical properties with special reference to agglomeration of TiO2-NPs. Our findings suggest that TiO2-NPs altered cytokine production, enhanced phagocytic indexing, metabolic stress through specific immune regulatory- genes expression in different WBC subsets and may contribute to pro-inflammatory response. Although TiO2-NPs have great advantages in the personal care products, biomedical, food and agricultural products, its chronic and acute immune-toxicity still need to be assessed carefully with special reference to food and environmental safety.

Keywords: TiO2 nanoparticles, oxidative stress, cytokine, human immune cells

Procedia PDF Downloads 381

Authors: Sangyeop Shin, D. C. M. Kulatunga, S. H. S. Dananjaya, Chamilani Nikapitiya, Jehee Lee, Mahanama De Zoysa

Abstract:

Saprolegniasis is one of the most devastating fungal diseases in freshwater fish which is caused by species in the genus Saprolegnia including Saprolegnia parasitica. In this study, we isolated the strain of S. parasitica from diseased rainbow trout in Korea. Morphological and molecular based identification confirmed that isolated fungi belong to the member of S. parasitica, supported by its typical fungal features including cotton-like whitish mycelium, zoospores (primary and secondary) and phylogenetic analysis with internal transcribed spacer (ITS) region. Pathogenicity of isolated S. parasitica was developed in embryo, larvae, juvenile and adult zebrafish as a disease model. Up regulation of host genes encoding ZfTnf-α, Zfc-Rel, ZfIl-12, ZfLyz-c, Zfβ-def, and ZfHsp-70 was identified in zebrafish larvae after experimental challenge of S. parasitica showing the host immune responses against the S. parasitica. Survival of the juveniles upon fungal infection might be due to the increased immune protection in the host. Investigation of antifungal susceptibility of S. parasitica with natural lawsone (2-hydroxy-1,4-naphthoquinone) revealed the minimum inhibitory concentration (MIC) and percentage inhibition of radial growth (PIRG %) as 200 µg/mL and 31.8%, respectively. Lawsone was able to change the membrane permeability, and cause irreversible damage and disintegration to the cellular membranes of S. parasitica which might have effect on fungi growth inhibition. Moreover, the mycelium exposed to lawsone (MIC level) changed the transcriptional responses of S. parasitica genes. Overall results indicate that lawsone could be a potential and novel anti-S. parasitica agent for controlling S. parasitica infection.

Keywords: host-pathogen interactions, lawsone, rainbow trout, Saprolegnia parasitica, Saprolegniasis, zebrafish

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Authors: Jiraporn Rojtinnakorn, Mallika Supa-Aksorn, Sudaporn Tongsiri, Prachaub Chaibu

Abstract:

Marble goby is one of high demand consuming in Southeast Asia. However, the product was from riparian fisheries because of low yield in aquaculture, especially in nursery stage. Therefore, we studied for herb supplement in pellet feed of marble goby fingering. Garlic, a common herb and illustrated novel pharmaceutical and medical effectiveness, was considered. Garlic extracts with water (DW), 50% EtOH (50E), 95% EtOH (95E) and diethyl ether (DE) were subjected for feed additive to induce immune response in marble goby fingering for 0 (control), 0.3, 0.5, 1.0, 3.0 and 5.0 % (w/w). After seven days of feeding, blood was collected for analysis of blood composition; i.e. haematocrit (HCT), red blood cells (RBC), white blood cells (WBC) and humoral immune responses; i.e. lysozyme activity (Lys). It was resulted that values of HCT, WBC and Lys in all garlic fed group were significantly different from control (p < 0.05). For HCT, the highest values belonged to 5% DW and 0.5% 95E. For WBC and Lys, the highest values were 5% DW. For RBC, there was not obviously significant (p < 0.05). There were only 3 groups; 0.5% 95E, 1% and 5% DW, showed distinct statistical significance from the other groups. It was concluded that garlic extracts showed satisfy bioactivity to enhancing innate immune response in marble goby fingering. This result will be valuable for specific feed formula of marble goby nursery.

Keywords: garlic extract, innate immune, marble goby, Oxyeleotris marmoratus

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Authors: Jiraporn Rojtinnakorn

Abstract:

ICAM-2 (intercellular adhesion molecule 2) or CD102 (Cluster of Differentiation 102) is type I trans-membrane glycoproteins, composing 2-9 immunoglobulin-like C2-type domains. ICAM-2 plays the particular role in immune response and cell surveillance. It is concerned in innate and specific immunity, cell survival signal, apoptosis, and anticancer. EST clone of ICAM-2, from P. gigas blood cell EST libraries, showed high identity to human ICAM-2 (92%) with conserve region of ICAM N-terminal domain and part of Ig superfamily. Gene and protein of ICAM-2 has been founded in mammals. This is the first report of ICAM-2 in fish.

Keywords: ICAM-2, CD102, Pangasianodon gigas, antitumor

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Authors: D. Bhowmik, Y. Tian, Q. Yin, F. Zhu

Abstract:

Cyclic GMP-AMP synthase (cGAS), recognises cytoplasmic double-stranded DNA (dsDNA), indicative of bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. Viruses also have developed numerous strategies to antagonize the cGAS-STING pathway. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human DNA tumor virus that is the causative agent of Kaposi’s sarcoma and several other malignancies. To persist in the host, consequently causing diseases, KSHV must overcome the host innate immune responses, including the cGAS-STING DNA sensing pathway. We already found that ORF52 or KicGAS (KSHV inhibitor of cGAS), an abundant and basic gamma herpesvirus-conserved tegument protein, directly inhibits cGAS enzymatic activity. To better understand the mechanism, we have performed the biochemical and structural characterization of full-length KicGAS and various mutants in regarding binding to DNA. We observed that KicGAS is capable of self-association and identified the critical residues involved in the oligomerization process. We also characterized the DNA-binding of KicGAS and found that KicGAS cooperatively oligomerizes along the length of the double stranded DNA, the highly conserved basic residues at the c-terminal disordered region are crucial for DNA recognition. Deficiency in oligomerization also affects DNA binding. Thus DNA binding by KicGAS sequesters DNA and prevents it from being detected by cGAS, consequently inhibiting cGAS activation. KicGAS homologues also inhibit cGAS efficiently, suggesting inhibition of cGAS is evolutionarily conserved mechanism among gamma herpesvirus. These results highlight the important viral strategy to evade this innate immune sensor.

Keywords: Kaposi's sarcoma-associated herpesvirus, KSHV, cGAS, DNA binding, inhibition

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