Day 1 :
Keynote Forum
Marco Sgarbanti
Italian National Institute of Health, Italy
Keynote: generation of cellular models to identify small molecule inhibitors of the anti-interferon proteins of human pathogenic RNA viruses
Time : 10:30-11:00
Biography:
Dr. Marco Sgarbanti has studied molecular virus-host interaction for 15 years as deducible by hispeer-reviewed publications. As researcher and principal investigator (PI), he has been studying the role of cellular transcription factors in HIV-1 LTR expression focusing on strategies aimed at eliminating viral reservoirs. Recently he has focused in the development of cellular assays suitable for high throughput screening (HTS) of small molecules, to find inhibitors of RNA viral proteins belonging to important human threatening virus diseases. Awards: winner of a Grand Challenges Exploration Grant in Global Health, Phase I,of the Bill & Melinda Gates Foundation.
Abstract:
The majority of emerging and re-emerging RNA viruses, responsible for life threatening diseases,have in common the ability to evade the innate immune responses mediated by type I interferon (IFN). This is mostly achieved through the expression of viral structural and non-structural proteins whose anti-IFN function isessential for virus replication.Such viral proteins have the ability to inhibit both the production and the ability of cells to respond to IFNs.Examples include the influenza viruses NS1 protein, West Nile virus NS2A, NS1 and NS4B proteins, Dengue virus NS5, NS2A, NS4A and NS4B proteins plus the NS2B/NS3 complex and Ebola virus VP35 and VP24 proteins.Therefore, the above mentioned viral proteins represent ideal targets for the development of antiviral compounds aimed at allowing innate immune responses to efficiently contain the initial viral replication and thus promoting the development of an effective adaptive immune response.This lecture will provide an overview on the RNA virus strategies to overcame the IFN system through the employment of viral gene products and will present data from our lab, describing the identification of two anti-influenza virus NS1 compoundsthrough a multidisciplinary approach involving a diverse library of small molecule and a reporter assay able to measure the inhibition of the anti-IFN activity of the NS1 protein.Moreover, the talk will discuss the generation of a myeloid cell model, that can be employed as a versatile module suitable for an high throughput screening of compounds potentially able to inhibit the function of RNA virus anti-IFN gene products, with a particular focus on the Ebola VP35 and VP24 proteinsfrom the on-going epidemic in West Africa.
- Workshop
Location: Barcelona, Spain
Session Introduction
Wolfgang W Leitner
Chief of the Innate Immunity Section
NIAID/NIH, USA
Title: Research funding by the US National Institutes of Health
Time : 11:15-12:15
Biography:
Wolfgang W Leitner is the Chief of the Innate Immunity Section, NIAID/NIH. He was involved in deciphering the mechanisms underlying the regeneration of splenic autotransplants and developed the first nucleic acid vaccine for P. berghei malaria. While establishing a replicase-based DNA vaccine for the treatment of melanoma, he uncovered the immune mechanism underlying the superior immunogenicity of aphavirus-based nucleic acid vaccines. He has authored more than 70 papers in the areas of vaccine research, basic immunology and cancer therapy. He joined the NIAID Extramural Program as a Program Officer in 2008 and oversees the innate immunity portfolio, including vaccine adjuvant research.
Abstract:
This lecture will guide the audience through the process of research funding by the US National Institutes of Health. The extramural program of the NIH provides approximately 1/3 of biomedical research funding in the US and also support numerous research projects overseas. Of the 27 NIH institutes, the NIAID is one of the two largest and responsible for research on infectious diseases, transplantation, various immune-mediated diseases as well as basic immunology. In addition to research on vaccines, the NIAID conducts and supports extensive research on vaccine adjuvants, immune mechanisms of protection, and the mechanism of action of adjuvant. The main funding mechanisms for pre-clinical research are the R01 research grant and the R21 exploratory grant for high risk/high reward research proposals. For most funding announcements, applications are accepted from non-US institutions and non-US citizens. To assist extramural investigators further, the NIAID provides numerous resources such as the tetramer core facility, BEI repository of biological reagents, computational resources, or the immune epitope database. The NIH Program Officer assigned to a specific research topic is the applicant’s primary point of contact and can help guide the applicant through the application, award and post-award process.
- Track 6:Plant Innate Immunity, Track 9: Inflammation, Track 12:Pathogen-specificity
Location: TER
Chair
Wolfgang W Leitner
NIAID/NIH, USA
Co-Chair
Marco Sgarbanti
Italian National Institute of Health, Italy
Session Introduction
Vladimir Litvak
University of Massachusetts Medical School, USA
Title: Metabolic and Epigenetic Reprogramming of Antiviral Immunity
Time : 12:15-12:40
Biography:
Dr. Litvak, assistant professor at UMMS, has studied immunology, metabolism and systems biology for 15+years and published his research papers in high-profile peer-reviewed journals such as Nature, Nature Immunology, Nature Cell Biology and Molecular Cell. He is an editor for the Immunome Research Journal. Dr. Litvak is a member of the Educational Resource Cluster at UMass Center for Microbiome Research. He also serves on the review committee for the National Center for Complementary and Alternative Medicine (NCCAM/NIH).
Abstract:
This lecture will introduce the emerging field of immunometabolism and will cover a range of topics addressing the role of metabolic networks in the regulation of antiviral immunity. The lecture will emphasize the function of central metabolic pathways in the epigenetic reprogramming of innate antiviral immunity and will discuss its contribution to the balance of beneficial effects and deleterious sequelae of the antiviral response. In addition, this lecture will present a variety of systems biology approaches and will highlight their importance as a powerful tool in the analysis of complex immune-metabolic interactions. Finaly, attendees of this lecture will be familiarized with an application of the systems biology approach to the discovery of new drug targets for the therapeutic control of viral infections or autoimmune disease.
Jürgen Bernhagen
RWTH Aachen University, Germany
Title: The emerging role of innate chemokines in inflammatory disease and atherosclerosis
Time : 12:40-13:05
Biography:
Professor Bernhagen studied Biochemistry and Immunology at the University of Tübingen, Germany, and at Queen Mary College, London, UK. He performed a sandwich PhD thesis at the University of Tübingen and at the Picower Institute for Medical Research, Manhasset, NY, USA, and was trained as a postdoc at the Picower. Professor Bernhagen currently is a Full Professor of Biochemistry and Molecular Cell Biology at RWTH Aachen University, Germany, and is the Chair and Director of the homonymous institute. His main research interest has been on cytokines, chemokines and their role in inflammation, with a focus on MIF and the biochemical and structural features and mechanisms of such inflammatory mediators. He also studies the COP9 signalosome. Studied disease models encompass rodent model of atherosclerosis, sepsis, liver and kidney disease as well as colitis and colorectal cancer. Professor Bernhagen has authored more than 120 peer-reviewed papers in these areas, several of them published in leading journals such as Nature, Nature Medicine, or PNAS. He has serves on the editorial board of several journals and serves on several review committees for extramural funding and various fellowship organizations.
Abstract:
Inflammatory processes such as those promoting atherosclerotic lesion formation are pivotely driven components of the innate and adaptive immune axis. Chemokines and their receptors are a particularly prominent part of the innate immune arm. While the role of classical chemokines, i.e. belonging to the CC or CXC families, is increasingly well understood, it also has become clear that the underlying ligand/receptor system is characterized by a previously unanticipated complexity of cross-reactivities and homo- and heteromerization events. Moreover, an emerging family of chemokine-like inflammatory mediators termed ‘innate chemokines’, CLF chemokines or micro-chemokines, which additionally struc¬turally and functionally overlaps with the mediator class of alarmins has been identified to modulate inflammatory reactions in the atherogenic arterial wall but also numerous other inflamed tissues. Innate or CLF chemokines share functional homology with classical chemokines and signal through classical chemokine receptors, whereas they do not exhibit conserved structural features such as N-terminal tandem cysteine residues or the chemokine fold. This lecture will address the molecular basis of target cell activity and the pathophysiological role of several ‘innate chemokines’. Examples will encompass high mobility group binding protein-1 (HMGB1), macrophage migration inhibitory factor (MIF), and certain ï¢-defensins. Receptor usage, signaling, innate immune cell regulation, and involvement in various inflammatory conditions, including atherosclerosis will be discussed. Finally, the lecture will outline potential strategies to specifically and thera¬peutically target such mediators either in conjunction or explicit exclusion of the co-targeting of classical chemokines.
Anwen S Williams
Cardiff University School of Medicine,United Kingdom
Title: Pre-clinical evaluation of an Interleukin- 6 antagonist in inflammatory arthritis
Time : 13:50-14:15
Biography:
Dr Anwen Siân Williams completed her PhD at the age of 25 years from the University of Wales Institute of Science and Technology and postdoctoral studies from Cardiff University. She is a pharmacist and senior member of the academic staff at Cardiff University’s School of Medicine. Dr Williams is a biomedical research expert who has published over 60 papers in reputed journals. She leads a successful scientific research programme within the Institute of Infection and Immunity that is aimed at delivering excellent teaching and learning opportunities for undergraduate and postgraduate students that is centred upon the study of arthritis.
Abstract:
The cellular and molecular signals that safeguard the architecture of the joint during an acute flare of inflammatory arthritis are ill defined. Published data from our group clearly identifies interleukin-6 (IL-6) signaling pathway as important factors that alter early inflammation, tissue homeostasis and tissue damage (1-3). We use relevant cell-based in vitro assays and in vivo models to assign specific IL-6 mediated molecular mechanisms that regulate degenerative cell functionality. We also explore the potential value of a pertinent IL-6-directed antagonist as a preventative therapy for early joint injury during experimental inflammatory arthritis. The manner by which the IL-6 pathway regulates cell trafficking during arthritis is characterized and its impact upon bone homeostasis is assessed.
Madan K. Bhattacharyya
Iowa State University, USA
Title: Identification and application of nonhost immunity mechanisms for creating broad-spectrum disease resistance in crop plants
Time : 14:15-14:40
Biography:
Bhattacharyya received his Ph.D. in Plant Science from the University of Western Ontario, Canada. Following his graduate studies, he joined John Innes Institute, England for his postdoctoral research and isolated the rugosus locus studied by Gregor Mendel. His group has been engaged in conducting research in the area of plant disease resistance with a goal to enhance broad-spectrum disease resistance in soybean. Currently, he directs a multiinstitutional research project funded by USDA-NIFA. He has published over 60 scientif papers mostly in high profile journals. He serves several journals including BMC Plant Biology, BMC Genomics, Molecular Biotechnology, Frontiers in Agricultural Biological Chemistry, and Journal of Plant Genome Sciences for editorial duties.
Abstract:
We are surrounded by innumerable number of pathogenic organisms. Fortunately, we are infected by only a few organisms. Crop plants also encounter a large number of microorganisms on a daily basis; only a few of which are pathogenic. A crop plant has the ability to defend pathogens of all other crop species due to their nonhost immunity mechanisms. For example, soybean is immune to maize pathogens; whereas, maize is immune to soybean pathogens. Nonhost resistance mechanisms are broad-spectrum and durable. Therefore, utilization of nonhost resistance mechanisms has been considered to be ideal for enhancing disease resistance in crop plants. We tested this hypothesis by identifying and then transferring Arabidopsis nonhost resistance genes to soybean. We selected two soybean pathogens: the oomycete pathogen, Phytophthora sojae, and the fungal pathogen, Fusarium virguliforme, for this study. Both are serious soybean pathogens. Together, they can cause soybean yield suppression valued up to half-a-billion US dollars. We have isolated 30 putative P. sojae-susceptible (pss) Arabidopsis mutants. Among 30 pss mutants, 14 were also susceptible to F. virguliforme. We have cloned five Arabidopsis nonhost resistance genes by utilizing six of these 14 selected pss mutants. We have transferred two of these genes encoding a glycine-rich protein and a folate transporter to soybean. Transgenic soybean plants carrying these genes are resistant to both P. sojae and F. virguliforme. Thus, our results confirm the applicability of nonhost resistance mechanisms for creating broad-spectrum disease resistance in crop plants. We have also demonstrated that folate is essential for nonhost immunity
Jim Middleton
University of Bristol, Bristol, UK
Title: Novel therapeutic approach to inhibit innate immune cell trafficking in inflammation using chemokines and their binding molecules.
Time : 14:40-15:05
Biography:
Prof Middleton completed his PhD at Lancater University and postdoc research at Cambridge and Bath before working as Senior Scientist in inflammation biology with Novartis (Vienna). He obtained an academic position in Keele University where he became Senior Lecturer, Reader and Professor of Immunology. Currently he is Professor and Reader of Immunology at the University of Bristol. Prof Middleton was a Visiting Professor at CNRS, Toulouse, and has acted as consultant for GSK and biotech industry. He is on the editorial board for Arthritis Research and Therapy and has published in Cell, J Exp Med, Nature Immunol, and J Immunol.
Abstract:
Chemokines are involved in driving leukocyte migration into inflamed tissue. They achieve this by being presented to blood leukocytes by heparan sulphate proteoglycans (HSPGs) on the luminal surface of vascular endothelial cells. We have found that in the synovial endothelial cells of rheumatoid arthritis patients there is induction of a CXCL8 binding site on the HSPG syndecan-3. This suggests involvement of syndecan-3 in leukocyte trafficking into the synovium. Indeed we have shown that leukocyte accumulation and cartilage damage is reduced in syndecan-3 null mice with antigen-induced arthritis. Addition of soluble syndecan-3 in vitro binds chemokines CCL2 and CCL7, and redcues chemotactic responses of moncytes to these chemokines. Injection of soluble syndecan-3 reduces leukocyte accumulation and arthritis severity in antigen-induced arthritis. HSPGs interact with basic residues in chemokines. Therefore addition of competing peptides containing these residues should be inhibitory. Indeed we have found some chemokine peptides do inhibit chemokine-HSPG interaction. These peptides bind HS and inhibit chemokine-driven migration of neutrophils across brain microvascular endothelial cells in vitro. Furthermore these chemokine peptides reduce the swelling of joints of mice with antigen-induced arthritis. In conclusion targeting chemokine-HSPG interactions by adding competing soluble HSPGs (syndecans) and chemokine peptides have therapeutic effects and represents a novel therapeutic approach to inhibit innate immune cell trafficking.
Cécile Oury
GIGA, University of Liège,Belgium
Title: Interplay between inflammation, immunity and thrombosis: role of platelet and neutrophil P2X1 receptors
Time : 15:05-15:30
Biography:
Dr Cécile Oury, PhD in Biology, has studied platelet biology for 15 years. In 2001, she was the laureate of the prize Boerhinger Ingelheim for her research on Thrombosis and Haemostasis. She is now Research Associate at the Belgium Fund for Scientific Research, and she is the Head of the Laboratory of Thrombosis and Haemostasis, part of the Unit GIGA-Cardiovascular Sciences at the University of Liège, Belgium. GIGA is an interdisciplinary institute comprising >250 scientists active in biomedicine. Dr Oury’s research focuses on the elucidation of the mechanisms of thrombosis using in vitro studies and animal models. She has a h-index of 18, more than 50 international peer-reviewed papers and 1434 citations. Dr Oury is a Council member of the Belgian Society on Thrombosis and Haemostasis and a member of the International Society on Thrombosis and Haemostasis
Abstract:
This lecture will present the latest findings on the contribution of innate immune cells in thrombosis. It will also address the recent view of platelets as rapid first-line immune responders. Focus will be made on the role of P2X1 receptors for extracellular ATP. It has long been recognized that inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between inflammation and thrombosis. On platelets, P2X1 receptors act to amplify platelet activation and aggregation induced by other platelet agonists. These receptors critically contribute to thrombus stability in small arteries. Besides platelets, studies by our group indicate that these receptors are expressed by neutrophils. They promote neutrophil chemotaxis, both in vitro and in vivo. In a laser-induced injury mouse model of thrombosis, it appears that neutrophils are required to initiate thrombus formation and coagulation activation on inflamed arteriolar endothelia. In this model, by using P2X1-/- mice, we recently showed that P2X1 receptors, expressed on platelets and neutrophils, play a key role in thrombus growth and fibrin generation. Taken together, these data suggest that P2X1 receptors are involved in the interplay between platelets and neutrophils. Activation of these receptors by ATP on neutrophils and platelets might be involved in the regulation of inflammation, immunity and thrombosis.
Alejandra Pera
University of Córdoba, Spain
Title: Effect of age and CMV infecton on NK cell subsets and phenotype
Time : 15:30-15:55
Biography:
Alejandra Pera performed her PhD studies at the Ramón y Cajal University Hospital (Madrid) and at the Università degli Studi of Milan, in 2009. Ever since, she has foccused her work on immunosenescence, particularly on the effect of CMV and age on NK and T cells’ phenotype and function. She has authored several works regarding this topic this year. As well, she has colaborated recently with Dr. Larbi at the Singapore Immunology Network and currently has a Juan de la Cierva postdoctoral contract (Ministry of Science and innovation).
Abstract:
The main topic of this lecture will be based on the current knowledge on age-associated phenotypic and functional changes in NK cells and the role of persistent CMV infection. It will be disclosed the key role of NK cells in the innate immune response against virus infection and tumors. Besides, attendees of this lecture will be familiarized with NK cell subpopulations based on CD56 and CD16 markers expression and the NK cell compartment remodeling in the elderly. As well, it will be shown how age and CMV infection have an effect on the expression of CD57, CD94/NKG2C, activating natural cytotoxicity receptors (NCRs, NKp30, NKp46) and DNAM-1. In summary it will be disscused how NK cell subsets and their phenotype in the elderly are afected not only by age but also by exposure to CMV and the relevance of including the determination of CMV serostatus in those studies addressed to analyze the effect of age on NK cell phenotype and function.
Cheol-Heui YUN
Seoul National University, Seoul, Republic of Korea
Title: Alveolar macrophages treated with bioparticles, mediated through MyD88-dependent mannaer, are indispensable for the protection in mice infected with respiratory syncytial virus A2
Time : 16:10-16:35
Biography:
Professor Cheol-Heui YUN completed his Ph. D. at the University of Saskatchewan, Canada in the area of immune modulation and mucosal immunology. Then, he pursued his professional career at different part of the world including International Vaccine Institute, Korea; USDA, USA; NIH, USA and Gothernburg University, Sweden. He has published more than 150 papers in reputed journals and serves as editor of many societies including World Journal of Immunology, Frontiers in Molecular Innate Immunity, Journal of Biomaterials and Tissue Engineering. Currently, he is a president of Korean Dendritic Cell Academic Society. His interest has focused on relationship between mucosal immune respnses regarding infectious diseases and vaccine/adjuvant.
Abstract:
Alveolar macrophages treated with bioparticles, mediated through MyD88-dependent manner, are indispensable for the protection in mice infected with respiratory syncytial virus A2 (E-BABE): Respiratory syncytial virus (RSV) causes a common respiratory disease. But we have no effective ways to prevent RSV infection until now. Indeed, poor innate defense mechanisms at the initial stage of the infection brought about the serious consequences in RSV infection. One of the primary innate immune cells in the lung is alveolar macrophages (AM), which play a pivotal role to maintain homeostasis at rest and induce effective defense mechanism against infectious disease. However, a precise function of AM in RSV infected mice remains unclear. We here report that bioparticles derived from Bacillus subtilis could induce the activation of AM that played a critical function in protection against RSV infection. These bioparticels induced innate immune responses, increasing number of AM coincident with enhancing GM-CSF and IFN-γ, known as differentiation factors for classically activated macrophages (M1-macrophages). Selective depletion of AM in wild-type mice or MyD88 knock mice failed to induce IL-12p40 and impaired the clearance of dead cells associated with severe morbidity during RSV infection. Taken together, our results suggest a definitive role of AM induced by bioparticels derived Bacillus subtilis in protection from RSV infection. Biography Professor Cheol-Heui YUN completed his Ph. D. at the University of Saskatchewan, Canada in the area of immune modulation and mucosal immunology. Then, he pursued his professional career at different part of the world including International Vaccine Institute, Korea; USDA, USA; NIH, USA and Gothernburg University, Sweden. He has published more than 150 papers in reputed journals and serves as editor of many societies including World Journal of Immunology, Frontiers in Molecular Innate Immunity, Journal of Biomaterials and Tissue Engineering. Currently, he is a president of Korean Dendritic Cell Academic Society. His interest has focused on relationship between mucosal immune respnses regarding infectious diseases and vaccine/adjuvant.
Oziniel Ruzvidzo
North-West University,South Africa
Title: Plant Adenylate Cyclases - Elucidation of their Potential Roles in Stress Response and Disease Resistance Mechanisms
Time : 16:35-17:00
Biography:
Professor Oziniel Ruzvidzo completed his doctoral degree in Plant Biotechnology in 2009 at the University of the Western Cape, South Africa. He also undertook some postdoctoral studies in the same subject area in 2010 at the University of Cape Town in South Africa. Currently, he is the Head of Department and Principal Investigator of Plant Biotechnology in the Department of Biological Sciences at the North-West University, Mafikeng Campus, South Africa, where he has already extensively published high impact factor papers in this subject area of his research specialization. Professor Ruzvidzo is an active member of several university committees including the senate as well as an editorial member of various academic and research boards locally, regionally and internationally.
Abstract:
Adenylate cyclases (ACs) are enzymes capable of converting the cellular molecule adenosine 5′-triphosphate (ATP) to the second messenger cyclic 3′,5′-adenosine monophosphate (cAMP) (Robison et al., 1968). Apparently, while in animals and other lower eukaryotes, ACs and their cAMP have firmly been established as important signaling molecules with critical roles in cellular processes like signal transduction and stress response (Gerisch et al., 1975), in higher plants however, only 4 ACs have so far been practically and experimentally confirmed. These are the Zea mays pollen protein responsible for the polarized pollen growth (Moutinho et al., 2001), the Arabidopsis thaliana pentatricopeptide repeat protein responsible for pathogen responses and gene expressions (Ruzvidzo et al., 2013), the Nicotiana benthamiana adenylyl cyclase protein responsible for the tabtoxinine-β-lactam-induced cell deaths during wildfire diseases (Ito et al., 2014), and the Hippeastrum hybridum adenylyl cyclase protein involved in stress signalling (Swiezawska et al., 2014). With continued work in this specific field domain, a recent study has further propossed an array of at least 14 other AC-encoding gene candidates in the Arabidopsis genome, and based on the functionally assigned amino acids in the catalytic center of annotated and/or experimentally tested nucleotide cyclases in lower and higher eukaryotes (Gehring, 2010). Our work therefore, is presently involved in the recombinant expression and functional characterization of these proposed AC genes to try and elucidate their possible physiological roles in stress response and disease resistance mechanisms. To date, 4 of these candidate genes have already been fully characterized, with some intriguing outcomes, while more work is still underway with the rest of the other genes.