BRIDGING THE GAP 2011 · BRIDGING THE GAP 2011BRIDGING THE GAP 2013 WELCOME MESSAGE Dear participants, Once again it is our – the student organizing committee’s – pleasure to

BRIDGING THE GAP 2011BRIDGING THE GAP 2013

We thank the following sponsors for their generous support:


WELCOME MESSAGE Dear participants,

It has already become a tradition that student members of the International Ph.D. program in "Cell Communication in Health and Disease" (CCHD) of the Medical University of Vienna organize the international „Bridging the Gap“ workshop that will take place for the 6th time at our university.

Talking about life – it`s all about communication. On the one hand, this principle is reflected in our outstanding PhD program „Cell Communication in Health and Disease" which is co‐financed by the Austrian Science Fund and the Medical University of Vienna. This program offers students the opportunity to acquire skills that can be employed in highly divergent areas, by exposing them ‐ within a single multidisciplinary framework ‐ to four research themes that deal with organ‐independent ubiquitous regulatory systems: neurobiology; vascular biology; immunology; and inflammation research. On the other hand, this principle is reflected in the collaborative structure of the program which enables participants to strengthen ties among and between scientists of different fields, between students and researchers, between students from diverse backgrounds and thus, to promote a greater integration of the disciplines.

Our PhD program that embraces multiple complementary attitudes and approaches to science is the greatest opportunity to create a young generation of researchers with sufficient expertise and flexibility to network, communicate and promote scientific knowledge.

I would like to thank the students for organizing the 6th CCHD workshop and for compiling an exciting program including distinguished international speakers.

I wish all of you an inspiring workshop!

Karin Gutiérrez‐Lobos

Vice Rector for Education, Gender & Diversity, MUV


WELCOME MESSAGE In order to offer cutting‐edge patient treatment, providers of medical care must not only act in the wards but also in the laboratories. At the Medical University of Vienna, which also runs the Vienna General Hospital, we believe that by schooling students in medicine they will learn to provide effective relief to patients, but by additionally training them in science, they might move on to discover cures. To this end, we study the underlying causes for disease by focusing on how cells exchange vital information. Our doctoral training program “Cell Communication in Health and Disease” (CCHD) provides students with challenging research projects that range from basic biomedical sciences to translation into clinical application. CCHD gives students the opportunity to acquire skills that can be employed in highly divergent areas, by exposing them ‐ within a single multidisciplinary framework ‐ to four research themes that deal with organ‐independent ubiquitous regulatory systems: neurobiology; vascular biology; immunology; and inflammation research.

CCHD being in its seventh year gives us the opportunity to have our Sixth International Workshop of Cell Communication in Health and Disease. As in previous years, this meeting is organized by the 19 students who currently are part of CCHD. In accordance with scientific multidisciplinarity as the major asset of CCHD, this workshop brings together experts in the four CCHD research topics with the aim of bridging the gap. The highly interesting program spans from the pathophysiology of hepatitis C to the role of lymphatic vessels in cancer and from the importance of chemokines for immune cells to the mechanisms of action of caffeine. I would like to thank the students for putting together this program and our guests for accepting the students’ invitations in order to share their results and expertise with us. I look forward to illuminative seminars and lively discussions and I do hope that not only the CCHD students, but also all other participants will keep this CCHD workshop in mind as unforgettable event.

Stefan Böhm

Coordinator of CCHD


WELCOME MESSAGE Dear participants,

Once again it is our – the student organizing committee’s – pleasure to invite you to our annual Bridging the Gap (BTG) symposium. In line with the interdisciplinary philosophy of our Cell Communication in Health and Disease (CCHD) Ph.D. program, we sought to compile an up‐to‐date program, covering important developments and hot topics from neurobiology, vascular biology, immunology and inflammation research. To this effect, we are proud to present you with 12 international top scientists from Europe and overseas who have made – and continue to make – important contributions to these fields. This year’s program features such seemingly diverse topics as tumor escape mechanisms, neuronal signaling and control of infectious diseases. However, in a biological system all of these aspects of molecular research are interconnected with each other – something we want to reemphasize in today’s highly specialized science business.

Being in its sixth year, the BTG symposium is now a regular feature of Vienna’s varied conference schedule. This is not only due to the outstanding presentations and diligent preparation of speakers and organizers of the past. Essentially, our workshop depends on the active participation of the audience. We encourage all of you to take part in the discussions during (as well as in between) the scientific sessions. Thus we hope to bridge the gap – not only between different disciplines of research, but also between the representatives of said disciplines, professors and students alike.

Having said this, we hope you enjoy the selection of talks assorted for 2013. In addition, do not hesitate to address us during the meeting to comment and give us your feedback.

Also at this year’s BTG workshop, life is all about communication.

The Organizing Committee


PROGRAM


Chairs of session Day 1 Wednesday 13th February

Program Topic

9:30‐10:00 Registration & Coffee Opening of the 6th CCHD Symposium

Session I

Michael Freissmuth 10:00‐11:00 Bertil Fredholm Caffeine, Adenosine and the Brain

Thomas Klausberger 11:00‐12:00 Susan Jones Glutamate Receptors in Midbrain Dopaminergic Neurons

12:00‐13:00 Lunch

Session II

Hans Lassmann 13:00‐14:00 Sam David Iron Efflux Mechanisms in Glia and their Role in Neural Damage and Repair

Monika Bradl 14:00‐15:00 Katerina Akassoglou The Role of Fibrin in Microglia Activation and Axonal Damage in Neuroinflammation

15:00‐15:30 Coffee break

Session III

Dontscho Kerjaschki 15:30‐16:30 Reinhold Förster Visualization of Cytotoxic CD8 T Cell Swarm Hunting and Viral MHC I Immune Evasion

Brigitte Hantusch 16:30‐17:30 Melody Swartz Tumor‐Associated Lymphatic Vessels: More than an Escape Route


Chairs of session Day 2 Thursday 14th February

Program Topic

Session IV

Barbara Herdy 9:00‐10:00 Charles Rice Hepatitis C: Is the End in Sight?

Sylvia Knapp 10:00‐11:00 Leif Erik Sander Innate Immune Recognition of Infectious Threats


Session V

Christine Mannhalter 11:30‐12:30 Ellinor Peerschke Platelets, Complement and Thrombosis

12:30‐13:30 Lunch

Session VI

Erika Jensen‐Jarolim 13:30‐14:30 Marc Veldhoen Intestinal Immunity Marches on its Stomach

Hannes Stockinger 14:30‐15:30 Antonella Viola Chemokines and T Cell Activation


Session VII

Stefan Böhm 16:00‐17:00 Peter Århem Ion Channels and Neuronal Impulse Patterns

17:00‐17:15 Closing of the 6th CCHD symposium


ABSTRACTS


Bertil B. Fredholm Department of Physiology and Pharmacology, Karolinska Institutet, S‐17177 Stockholm, Sweden

Caffeine, adenosine and the brain Caffeine is the most widely used of all drugs. The reason is its effects on the central nervous system. In lower doses those effects can be explained by blockade of adenosine receptors. These receptors are four in all mammalian species: A1, A2a, A2B and A3. The first three are potently inhibited by caffeine, but the fourth requires toxic doses. The A1 and A2A receptors show high affinity for adenosine, whereas A2B receptors require higher levels. Such levels are rarely seen in the brain under physiological conditions. Thus caffeine probably acts by blocking CNS A1 and A2A receptors. I will demonstrate how caffeine acts to alert us and wake us up by blocking A2A receptors and specifically A2A receptors in the nucleus accumbens shell. Activation of both A1 and A2A receptors can induce sleep, but these effects are exerted elsewhere. A2a receptors are also important in other dopaminergic transmission and play a role in Parkinson’s disease. A1 receptors regulate transmitter release and are important in reducing epilepsy. Indeed activation of A1 receptor signaling appears to be a way to treat even severe epilepsy. I will also briefly touch upon the effects on pain and the role of the adenosine system in ischemia.

Professor Bertil B. Fredholm obtained his Medical Degree in 1970 at the Karolinska Institutet, Stockholm, Sweden. He acquired post‐doctoral experience in laboratories all over the world, including San Diego, Denver, Dallas, Buenos Aires and Kobe (Japan). Afterwards, he moved back to Karolinska Institutet, where in 1977 he became a

Professor of Pharmacology. Prof. Fredholm is an

internationally renowned specialist in the field of adenosine and its receptors. He holds numerous academy memberships and honours, i.a. he was awarded the ECNP Neuropsychopharmacology Award in Basic Science Research in 2011 for his pioneering work on brain adenosine and the actions of caffeine. For several years he was a member and a chairman of the Nobel Prize Committee, as well as a chairman of IUPHAR committees and the Department of Physiology and Pharmacology of the Karolinska Institutet. Prof. Fredholm holds many memberships in editorial and scientific advisory boards. As a highly cited scientist, he is author of 520 original publications in peer reviewed international journals with

more than 28000 citations.


Susan Jones Department of Physiology, Development and Neuroscience, University of Cambridge, UK

Glutamate receptors in midbrain dopaminergic neurones Dopamine‐releasing (DA) neurones in the basal ganglia of the mammalian brain are thought to encode information about important environmental stimuli, such as rewards (or cues that signal rewards), and they contribute to the initiation of appropriate motor responses. DA neurones are affected in a number of brain disorders, including Parkinson’s disease (PD) and drug addiction. Glutamatergic input drives DA neuronal firing and in my lab we study the types, properties and regulation of glutamate receptors in DA neurones, including AMPA and NMDA ionotropic glutamate receptors. I will present some of our work on the types and properties of ionotropic glutamate receptors that could contribute to calcium influx in DA neurones. Glutamate receptor‐mediated calcium influx can activate intracellular signalling pathways important for neuronal development, plasticity and survival, but can also lead to excitotoxicity and cell death.

My research interest is the modulation of neuronal activity by neurotransmitters, signalling molecules and drugs, because by such mechanisms the nervous system is transiently or persistently altered for physiological, pathophysiological or therapeutic purposes. I carried out my PhD work in Professor David Brown’s lab at University College London, studying potassium channel modulation by G protein‐coupled receptors. I then focussed on glutamate‐, serotonin‐ and acetylcholine‐gated ion channel receptors during postdoctoral research in the USA with Dr Jerrel Yakel (NIH) and Dr Julie Kauer (Duke University and Brown University). In Dr Kauer’s lab I began working on DA neurones and I continued to work on these cells when I started my lab at the University of Cambridge in 2002. We use cellular neurophysiology, pharmacology and imaging approaches to study the properties of individual receptors, synaptic function, neuromodulation and plasticity. Our recent work has focused on the properties and regulation of NMDA glutamate receptors in the substantia nigra.


Samuel David Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.

Iron efflux mechanisms in glia and their role in neural damage and repair Iron is required for many metabolic processes and is essential for life. On the other hand excess iron can be toxic as it can generate free radicals and cause cell death. Iron homeostasis in cells therefore needs to be tightly regulated. Dysregulation of iron homeostasis is seen in various neurological conditions. This talk will focus on iron efflux mechanisms. Iron efflux is mediated by the interaction between the iron transporter, ferroportin and ferroxidases. In the CNS, the ferroxidase ceruloplasmin (Cp) is normally expressed by astrocytes, while hephaestin (Heph) is expressed by oligodendrocytes. Microglia/macrophages express both. Mice and humans lacking Cp (aceruloplasminemia) show iron accumulation in astrocytes with age, accompanied by loss of astrocytes and neurons. The neuronal loss is not due to iron accumulation in neurons but likely due to loss of metabolic support from astrocytes or from neuronal iron starvation. Lack of Heph in the naturally occurring sla mouse mutant leads to iron accumulation in oligodendrocytes in grey but not white matter, and is accompanied by a subtle defect in paranodal loops of myelin that may contribute to the loss of motor control. The sparing of white matter oligodendrocytes in sla mice is due to upregulation of Cp expression in white matter oligodendrocytes. Double mutants lacking both Heph and Cp show iron accumulation in both grey and white matter. In other work, we show that iron efflux from astrocytes via ferroportin contributes to remyelination in a model of chemically‐induced demyelination. Finally, lack of iron efflux from Schwann cells in Cp null mice leads to iron accumulation in Schwann cells in the sciatic nerve and impaired axon regeneration. Cell culture studies show that iron is required for the initiation and extension of neurites. These studies highlight the important role of iron efflux from glia in neurodegeneration and repair.

Dr. Sam David is a Professor in the Department of Neurology and Neurosurgery, at the Centre for Research in Neuroscience, Research Institute of the McGill University Health Center in Montreal. He obtained his PhD degree in 1979 from the University of Manitoba, and did postdoctoral work at McGill University and University College London, UK. His research focuses on molecular mechanisms of inflammation after spinal cord and peripheral nerve injuries, CNS autoimmune disease and the molecular control of iron homeostasis in the CNS and its dysregulation in CNS pathologies. He has published in top tier journals such as Science, PNAS, Neuron, Nature Immunology, Nature Reviews Neuroscience, Brain, and Journal of Neuroscience. He is Director of the CIHR Training Program in Neuroinflammation, which includes 16 laboratories at three Montreal area Universities. He is the current President of the Canadian Association of Neuroscience, member of the Medical Advisory Committee of the MS Society of Canada, member of the Scientific Advisory Board of Wings for Life Spinal Cord Research Foundation, and other scientific advisory committees.


Katerina Akassoglou Gladstone Institute of Neurological Disease, University of California, San Francisco, USA

The role of fibrin in microglia activation and axonal damage in neuroinflammation The blood protein fibrinogen as a ligand for integrin receptors functions as the molecular nexus of coagulation, inflammation and tissue repair. Fibrinogen extravasates in the nervous system after injury or disease associated with vascular damage or blood‐brain barrier (BBB) disruption. In multiple sclerosis (MS), perivascular demyelination is accompanied by increased vascular permeability resulting to extensive deposition of fibrin. Our studies in animal models for MS have demonstrated that fibrinogen is not merely a marker of BBB disruption, but a mediator of neuroinflammation. Fibrinogen mediates pro‐inflammatory and neurodegenerative functions in the nervous system by activating the Mac‐1 integrin receptor (also known as CD11b/CD18 and complement receptor 3) in microglial cells. In vivo imaging in the mouse spinal cord using two‐photon microscopy shows that microglia rapidly perform constant surveillance of blood vessel walls in myelinated areas and respond to fibrinogen by rapid and sustained process extension. Pharmacologic or genetic disruption of the fibrinogen/Mac‐1 interaction suppresses neurologic symptoms, inflammation, demyelination, and axonal damage in Experimental Autoimmune Excephalomyelitis (EAE), a model of MS. Because blocking fibrinogen/Mac‐1 interaction affects the proinflammatory but not the procoagulant properties of fibrinogen, strategies to target fibrinogen receptors within the tissue microenvironment could reveal selective and disease‐specific agents for therapeutic intervention in neuroinflammatory diseases.

Dr. Akassoglou has pioneered studies in the investigation of peripheral triggers of neurologic diseases, and in particular the role of the blood protein fibrinogen in CNS autoimmunity, trauma, and neurodegeneration. Her aim is to understand the mechanisms that control the communication between the brain, immune and vascular systems with the ultimate goal to design novel therapies for neurologic diseases—and in particular, multiple sclerosis. Her lab identified microglia as the major cell targets for fibrinogen in the CNS. Her research showed that it is possible to block the damaging effects of fibrinogen in the brain without affecting its beneficial effects in blood clotting. She also discovered novel roles for neurotrophin receptor signaling in metabolism and tissue repair. Dr. Akassoglou takes a multifaceted approach to her research, incorporating animal modeling, histopathology, in vivo two‐photon microscopy, tissue culture, and biochemistry techniques. Dr. Akassoglou

was awarded the Presidential Early Career Award for Scientists and Engineers, "the highest honor bestowed by the U.S. government on outstanding early‐career scientists and engineers", and the John J. Abel Award for "original and outstanding research contributions in pharmacology". Dr. Akassoglou earned a BSc degree in biology and a PhD in neurobiology at the University of Athens, Greece. She was trained in neuropathology by Hans Lassmann at the University of Vienna before performing her postdoctoral work at the State University of New York at Stony Brook, Rockefeller University with Sid Strickland, and New York University with Moses Chao. She is a Senior Investigator at the Gladstone Institute of Neurological Disease, and a Professor in the Department of Neurology at the University of California, San Francisco. She is also the Director of the Gladstone Center for In Vivo Imaging Research and Associate Adjunct Professor of Pharmacology at the University of California, San Diego.


Reinhold Förster Department at the Institute of Immunology at Hannover Medical School, Germany

Visualization of Cytotoxic CD8 T cell Swarm Hunting and Viral MHC I Immune Evasion Cytotoxic T cells are believed to efficiently kill virus‐infected target cells. Using various Mouse Cytomegalovirus (MCMV) reporter mutants and infection in mice we observed by 2‐Photon microscopy how both naïve and activated CD8 T cells interact with virus infected cells in intact mouse lymph nodes. Strikingly, viral MHC class I immune evasion encoded by MCMV (viral repressors of antigen presentation; vRAP) inhibited naïve CD8 T cell contact formation with MCMV‐infected lymph node stromal cells while cross‐presentation allowed for efficient CD8 T cell priming. During the effector phase, activated cytotoxic T cells attacked cells infected with MCMV mutants deficient for vRAP (MCMV‐DvRAP) but not wild type virus. Strikingly, the formation of small groups of 2‐3 motile CD8 T effector cells engaging a single virus infected cell at the same time predicted disruption of target cells. The direct visualizaton of virus‐infected cells and CD8 T effector cells allowed us to estimate per‐capita CD8 T effector killing rates of less than five virus‐infected cells killed per specific CD8 T cell per day. Notably, vRAP reduced this killing rate by another order of magnitude.

Reinhold Förster is Full Professor of Immunology and Head of the Institute of Immunology at Hannover Medical School. He studied Veterinary Medicine in Munich and Cambridge (UK) and graduated at the University of Munich in 1988 as a veterinary surgeon. In 1991, he obtained his doctorate in veterinary medicine summa cum laude with a dissertation in the laboratory of Prof. Anton Mayr on the role of pox viruses and pox virus protein on neutrophil function. From 1991‐1993, he stayed as a postdoctoral fellow in the laboratory of Prof. Ernst‐Ludwig Winnacker at the GenCenter at Munich University starting his work on chemokines and their receptors. From 1994 to 2000 he worked as a research associate at the Max‐Delbrueck‐Center for Molecular Medicine in Berlin. He obtained his Habilitation in 1998 at the Free University of Berlin. In 2000, he was appointed Associate Professor (C3) at the University Clinic for Surgery of

the University of Erlangen, and in 2001, he was appointed to his current position at MHH. Reinhold Forster is an internationally acknowledged expert on chemokines. Using gene targeting in mice he has published fundamental papers regarding the function of chemokine receptors such as CXCR5, CCR9 and CCR7 in Cell, Nature, Immunity and J. Exp. Med. His current interests lie in the identification of molecular mechanisms that control the migration of immune cells to and their positioning within lymphoid organs. In addition, he studies the role of sphingosine‐1‐phosphate receptors in lymphocyte homing and egress and addresses the role of steady state turnover of dendritic cells for the induction of peripheral tolerance. A further research project focuses on the molecular cues that guide developing T cell through the characteristic microenvironments of the thymus and their impact on negative selection. Further on, in vivo imaging of immunological processes in lymphoid organs by means of 2‐photon microscopy has been recently established in his lab and will fundamentally extent approaches used to study complex immune responses.


Melody Swartz Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland

Tumor‐associated lymphatic vessels: More than an escape route Lymphatic vessels drain fluid, antigens, and immune cells from the periphery to the lymph nodes (LNs). In addition to transporting activated dendritic cells to mount adaptive immune responses in the LN, lymphatic drainage brings soluble antigens from the periphery to LN‐resident immature dendritic cells and B cells. It is also the most common site for cancer metastasis. Despite its importance, the role of tumor‐associated lymphatic vessels and their drainage to the LN in regulating host immune responses to the tumor is poorly understood. We show that tumor expression of VEGF‐C, the most potent lymphatic growth factor, promotes pro‐tumor immune tolerance by several mechanisms. For one, it enhances drainage to the draining LN, where tumor antigens along with suppressive cytokines bathe the LN and could affect B and T cell education there. Second, tumor VEGF‐C upregulates CCL21 in the tumor stroma and surrounding lymphatic vessels, which itself promotes the infiltration of naïve T cells into the suppressive tumor microenvironment. Third, VEGF‐C drives expansion of peritumoral and LN lymphatic vessels, and we show that lymphatic endothelial cells can not only inhibit dendritic cell maturation and ability to activate anti‐tumor cytotoxic T cells, but also scavenge tumor antigen for direct cross‐presentation and cross‐tolerance of tumor‐reactive T cells. The combined effects of lymphatic expansion in the tumor microenvironment led to overall suppression of the effects of anti‐tumor immunotherapy. Together, these findings suggest that lymphatic drainage and inflammation‐induced lymphangiogenesis may serve to maintain peripheral tolerance to self‐antigens, and that tumors may hijack such mechanisms to escape host immunity.

Melody Swartz received her PhD in Chemical Engineering from M.I.T. in 1998 and, following a brief postdoc at Harvard / Brigham & Women’s Hospital, became Assistant Professor of Biomedical Engineering at Northwestern University in Chicago. In 2003 she was recruited to the EPFL and was promoted to Associate (2006) and then Full Professor (2010), with joint appointments in the Institute of Bioengineering and the Swiss Institute for Experimental Cancer Research (ISREC). Her lab uses in vivo, in vitro, and in silico models to study the complex and integrative functions of the lymphatic system and its role in cancer and immunity.


Charles M. Rice Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, USA

Hepatitis C: Is the end in sight? An estimated 200 million people have been infected with hepatitis C virus (HCV) with a majority unable to clear the virus. Chronic HCV infection can lead to cirrhosis, hepatocellular carcinoma, and end‐stage liver disease. It is generally believed that disease results at least in part from immune mediated inflammation. Since HCV’s discovery in 1989 significant progress has been made in establishing experimental systems and unraveling the details of the virus lifecycle. Examples include infectious molecular clones, RNA replicons and a robust cell culture system based on an HCV isolate from a rare case of acute fulminant hepatitis. Definition of the human factors required for HCV entry and blunting innate immune response pathways has led to the development of a mouse model that supports HCV entry, replication and virus production. Together these tools have increased our understanding of the HCV lifecycle and revealed multiple steps for therapeutic intervention. In 2011, two direct acting antivirals targeting the HCV serine protease were approved in combination with the previous standard of care, pegylated type I interferon and ribavirin. Even for the most difficult to treat HCV genotype (genotype I), more that 70% of patients can now be successfully treated. The future is even brighter with many compounds in the pipeline against both virus and host targets, raising hopes for an all oral interferon‐free regimen with a high cure rate.

Dr. Rice is the Maurice R. and Corinne P. Greenberg Chair in Virology and serves as Head of the Laboratory for Virology and Infectious Disease at Rockefeller University. He is one of the world’s most accomplished virologists and a prominent figure in research on members of the Flaviviridae including hepatitis C virus (HCV). Dr. Rice received his bachelor’s degree from University of California Davis in 1974 and earned his Ph.D. from California Institute of Technology in 1981. From 1986‐2000, Dr. Rice was a faculty member at Washington University in St. Louis. His research team has helped to understand the biogenesis and structure of HCV‐encoded proteins, discovered a highly conserved RNA element at the 3’ terminus of HCV genome RNA, and produced the first infectious molecular clone of the virus—an essential tool for future studies on this important human pathogen. His laboratory has established cell culture systems

and animal models for studying HCV replication and evaluating antiviral efficacy. Dr. Rice has co‐authored over 340 articles in the field of virology, serves as a reviewer for numerous journals, is a former editor of Journal of Virology, is a past President of the American Society for Virology, a Fellow of the American Association for the Advancement of Science, and a Member of the National Academy of Sciences. For more specific information about Dr. Rice’s research, please go to http://www.hepccenter.org


Leif Erik Sander Department of Infectious Diseases and Pulmonary Medicine, Charité University Hospital Berlin, Germany

Innate Immune Recognition of Infectious Threats Recognition of pathogen associated molecular patterns (PAMPs) enables the detection of microorganisms by the innate immune system and promotes immunity. However, inflammatory immune responses must be carefully dosed in order to minimize tissue damage and maintain self‐tolerance, while efficiently protecting the host organism against invading pathogens. Therefore, we proposed that immune responses are tightly scaled to the infectious threat of microbial encounters. For example, it is well appreciated that expression of virulence factors, such as bacterial secretion systems or toxins, imparts pathogenicity and strongly augments the resultant immune response. It is also known that infections or live vaccines often induce superior immunity compared to their dead counterparts. Yet, how these finer distinctions are made is less well understood. We could recently demonstrate an inherent ability of innate immune cells to actively distinguish between viable and dead bacteria, independently of their virulence. We identified a specialized class of PAMPs, called viability‐associated PAMPs (vita‐PAMPs), recognition of which signals microbial life to the immune system. Detection of bacterial viability, which is the quintessential basis of infectivity, triggers robust immune responses not warranted for dead microbes. Several concepts exist, as to how the immune system distinguishes between pathogenic and non‐pathogenic, or colonizing versus invasive microbes. Based on recent evidence, we have defined five immune checkpoints that collectively integrate information about the class of PAMP and the context of pattern recognition in order to evaluate the level of infectious threat. The result of this evaluation critically determines the magnitude and quality of the ensuing immune response. I will discuss recent advances and experimental evidence for the molecular basis of individual checkpoints and their impact on immunity. Deeper insight into the various risk assessment mechanisms will aid in the design of novel vaccines and adjuvant treatments for infectious diseases.

Dr. Leif Erik Sander graduated from Hannover Medical School in Germany in 2005 and received his PhD in the department of Gastroenterology and Hepatology at Hannover Medical School in 2006. He continued his training as a post‐doctoral fellow at the RWTH University Hospital Aachen (2006‐2008) and at the Mount Sinai School of Medicine in New York, NY (2008‐2011). In 2011, Leif joined the Charité University Hospital in Berlin as a principal investigator at the Dept. of Infectious Diseases & Pulmonary Medicine. His research is supported by the Emmy Noether Program of the DFG, the Else Kröner‐Fresenius Foundation and the Europoean Society of Clinical Microbiology and Infectious Diseases. In 2012, he was awarded the Theodor‐Frerichs Award of the German Society for Internal Medicine (DGIM).


Ellinor I. B. Peerschke Memorial Sloan‐Kettering Cancer Center and Weill Cornell Medical Center New York, New York, USA

Platelets, Complement and Thrombosis Platelets play an important role in hemostasis, thrombosis and inflammation. There is growing evidence that platelets interact with components of the complement system and that these interactions contribute to thrombotic complications. Our laboratory is focused on the pathophysiology of platelet receptors for the complement component C1q and their role in inflammation and thrombosis. Platelets express receptors both for the collagen tail and globular head domains of C1q, designated cC1qR and gC1qR, respectively. These binding sites may play important roles in immune complex clearance and clearance of apoptotic cell debris, as well as activation of complement, coagulation and kinin cascades. In vitro and in vivo studies suggest that the expression of cC1qR and gC1qR on platelets and their microparticles may contribute to the generation of proinflammatory and prothrombotic mediators at sites of vascular injury.

Dr. Ellinor Peerschke is Vice Chair of Laboratory Medicine and Head of Hematology and Coagulation Laboratory Services at Memorial Sloan Kettering Cancer Center in New York, NY. She is also Professor of Pathology and Laboratory Medicine at Weill Cornell Medical College in New York, NY. Dr. Peerschke received her Ph.D. degree in Basic Medical Sciences/Pathology from New York University in 1980 and has focused her career on integrating basic research with clinical laboratory practice in the hemostasis laboratory. Before joining Memorial Sloan Kettering in 2011, she directed Hematology and Coagulation Laboratory Services at Stony Brook University, Stony Brook, New York (1980‐1996), Weill Cornell Medical Center, New York, NY (1996‐2007), and the Mount Sinai Hospital and Medical Center, New York, NY (2007‐2011). She specializes in the evaluation of bleeding and thrombotic problems, particularly those arising from platelet function abnormalities. Her laboratory first described receptors for C1q on platelets and microparticles

and has contributed significantly to understanding the pathophysiology of platelet interactions with the complement system. Dr. Peerschke has been funded by the United States Public Health Service/ National Institutes of Health and the American Heart Association. She is currently focused on translational aspects of gC1qR expression in thrombosis and cancer.


Marc Veldhoen Department of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK

Intestinal immunity marches on its stomach It could be deemed appropriate to view terrestrial vertebrates as a combination of many species and their genetic build as a composite of genes embedded in their own genome and in the genomes of affiliated microbial partners: the microbiome. The body’s large surfaces, harbouring many resident commensals, are, however, also exposed to potentially harmful micro‐organisms. These surfaces include the skin and the gastro‐intestinal tract. Several barriers are in place to prevent microbes invading our bodies, the first of which is the epithelial cell layer. Although sufficient to prevent invasion by most microbes, this is not always adequate. A second line of defence is formed by cells of the immune system, providing protection against those microbes that overcome the epithelial barrier or which invade the body after trauma. Interestingly, many commensal micro‐organisms are highly beneficial to us and are instrumental in mediating physiologically important chemical transformations, whilst the cells of the epithelial barrier themselves are important for nutrient processing and uptake. Hence, an immune reaction at these sites needs to be tightly controlled and tailored to the potential threat‐level of the micro‐organisms detected (commensals vs. harmful opportunistic pathogens), with minimal damage to self, and with swift resolution and wound repair. Our laboratory studies the role that cells of the immune system play at the initiation, modulation and resolution of immune responses at epithelial barrier sites. These studies provide insights into the mechanisms that control the maintenance of a resident population of micro‐organisms, promoting healthy living, and the prevention of undesirable immune responses that may result in chronic infections, allergies, autoimmunity and an increased risk of cancer.

Marc Veldhoen studied Medical Biology at the Faculty of Medicine, Utrecht University, and continued his career in the Stockinger‐lab at the National Institute for Medical Research (Mill Hill) where he obtained his PhD in 2003. During his post‐doctoral work at the NIMR he was the first to describe the de novo differentiation of the new Th17 and Th9 subsets of T helper cells. He went on to show the importance of Th17 cells in the initiation of autoimmune responses, their plasticity, and, via the identification of the Aryl Hydrocarbon Receptor in Th17 and IL‐17 producing TCRγδ cells, established a link between the environment and auto‐immunity. In 2010 he moved to the Babraham Institute to take up a position as group leader. He continued his work on the AhR and discovered a direct link between dietary phytochemicals and the maintenance of epithelial immune cells. He was awarded a prestigious 2010 ERC Staring

Independent Research grant, and selected into the esteemed EMBO young investigator programme in 2011.


Antonella Viola Department of Adaptive Immunity, University of Milan and Humanitas Clinical and Research Center, Milan, Italy

Chemokines and T cell activation Chemokines are small cytokines with selective chemoattractant properties, coordinating the homeostatic circulation of leukocytes as well as their movement to sites of inflammation or injury. Dysregulated expression of chemokines and their receptors is involved in the development of many human diseases, including autoimmune and chronic inflammatory diseases as well as immunodeficiency and cancer. Because chemokine receptors are considered among the most druggable targets in the immune system, it is imperative to gain a deeper understanding of the complex biology of the chemokine biology in health and disease. Much has been learned about the chemokine system in the past years since their discovery as highly inducible genes and as chemotactic factors secreted from activated cells. However, novel aspects of the chemokine biology have recently emerged, indicating that chemokines have key roles in the initiation and execution of the adaptive immune response, through mechanisms that are only partially clear.

Antonella Viola got her Ph.D. in 1995 at the University of Padua (Italy) and then moved to Basel (Switzerland) to be a Scientific Member of the Basel Institute of Immunology. In 2001, she became PI at the Venetian Institute of Molecular Medicine (Italy) and in 2006 Head of the Adaptive Immunity Laboratories in FHR. She obtained several awards, including the Cancer Research Institute Investigator Award (New York, USA) and the EMBO YIP. Her research was and is supported by grants from Italy, EC, UK and USA and she coordinated eight collaborative projects. She was recently awarded an ERC Advanced Grant (2012). Her group studies signals modulating the immune response in health and diseases. Her major contributions to the

field are: the identification of the molecular mechanism allowing CD28 costimulation at the T cell immunological synapse (Science 273: 104‐6; Science 283: 680‐2; Nature Cell Biology, 8:1270‐1276; Nature Reviews Immunology, 7:889‐96); the definition of novel roles of chemokines in T cell biology (Nature Immunology, 6:465‐71; PNAS, 105:10101‐6; Annual Review of Pharmacology and Toxicology, 48:171‐97; Journal of Experimental Medicine, 203: 2879‐86; EMBO Journal, 29:4035‐47); the identification of new mechanisms responsible for cancer‐induced immunosuppression (Journal of Experimental Medicine, 201:1257‐68 and 208:1949‐62).


Peter Århem Department of Neurosience, Karolinska Institute, Stockholm, Sweden

Ion channels and neuronal impulse patterns The received view of neuroscience today is that each thought, each emotion (i.e. each mental state of the brain) correlate with specific oscillatory patterns of electrical impulses in networks of interacting neurons. The parameters shaping these patterns include inherent spiking dynamics of single neurons, functional connection strengths and network configuration. The impulse firing patterns of cortical neurons are remarkably robust, classifiable in some main types, including fast and regular spiking. The critical factors determining the inherent neuronal firing characteristics are poorly understood. Main factors suggested are the morphology of dendritic trees and the distribution and the combination of different ion channel types in the neuron membrane. Based on experimental (dynamic clamp on cortical cells) and mathematical (bifurcation theory and mathematical modelling) evidence we suggest a complementary explanation; the density of Na and K channels in the membrane determines the firing pattern. Altering the relative densities alters the spiking type. And altering the spiking type in groups of neurons alters the firing of the total network. From above it follows that pharmacological blocking of specific ion channels in brain neurons may alter brain firing patterns. Furthermore, it can be shown that different blocking mechanisms are associated with different modifications of the firing patterns. It is therefore of fundamental interest to study the blocking mechanisms of CNS active drugs to understand their action. One such mechanism is described by the modulated receptor hypothesis, today the prevalent view on local anaesthetic action. It states that local anesthetics preferentially bind to channels in the inactivated state. Based on both experimental and theoretical evidence, we suggest an alternative hypothesis; many local anaesthetics bind exclusively to the channel when in the open state. This hypothesis may better explain reported local anaesthetic effects on firing patterns. These novel suggestions will be discussed with reference to their relevance for understanding normal brain functioning (including consciousness) as well as a variety of neurological and psychiatric disorders (including altered awareness levels due to to general anaesthesia and psychopharmacological interventions).

Peter Århem is professor of neurophysiology at Karolinska Institutet, Stockholm. He defended his doctoral thesis in 1974, working on the voltage clamp method for myelinated fibres under Bernhard Frankenhaeuser. He spent a post‐doc period in the lab of Clay Armstrong in Woods Hole. His research today comprises mathematical and electrophysiological studies of the role of ion channels for neuronal impulse firing and of the mechanism of action of drugs on ion channels and G‐protein coupled receptors. In parallel with the experimental work he has also been involved in studies of more philosophical issues such as the brain‐mind problem. Thus he has published two conversations with the philosopher Karl Popper on the latter subject.


SPECIAL THANKS TO

Wolfgang Schütz Sylvia Knapp Sylvia Pagler Karin Gutiérrez‐Lobos Stefan Böhm

THE SPEAKERS

Bertil Fredholm Reinhold Förster Ellinor Peerschke Susan Jones Melody Swartz Marc Veldhoen Sam David Charles Rice Antonella Viola

Katerina Akassoglou Leif Sander Peter Århem THE CHAIRS

Michael Freissmuth Dontscho Kerjaschki Christine Mannhalter Thomas Klausberger Brigitte Hantusch Erika Jensen‐Jarolim Hans Lassmann Barbara Herdy Hannes Stockinger Monika Bradl Sylvia Knapp Stefan Böhm

AND

CeMM eBioscience® Medical University of Vienna FWF


THE ORGANIZING COMMITTEE


Barbara Maier [email protected]

Carol‐Ann Eberle [email protected]

Caroline Stremnitzer [email protected]

Cornelia Schuh [email protected]

Florian Koban [email protected]

Gabriel Wagner [email protected]

Hend Gafar [email protected]

Isabella Salzer [email protected]

Isabella Wimmer [email protected]

Itziar Arbesu [email protected]

Josefine Lindroos [email protected]

Justyna Kusek [email protected]

Marco Treven [email protected]

Markus Brown [email protected]

Michael Lagler [email protected]

Philipp Schatzlmaier [email protected]

Riem Gawish [email protected]

Simona Saluzzo [email protected]

Singer Josef [email protected]

http://www.meduniwien.ac.at/phd‐cchd




BRIDGING THE GAP 2011 · BRIDGING THE GAP 2011BRIDGING THE GAP 2013 WELCOME MESSAGE Dear participants, Once again it is our – the student organizing committee’s – pleasure to

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