2014 – The Great Escape

In 2014 the symposium’s theme was “The Great Escape”, which included various topics ranging from bacterial antibiotic resistance and immune evasion strategies to molecular mechanisms of autoimmune diseases and cancer. The aim was to highlight aspects on the escape from host immune surveillance by micro-organisms to the rescue from infection and disease by infected hosts. The symposium took place on 20 & 21 November 2014. Workshops  Scientific  Prof. dr. W.A. Paxton – Genotypes and phenotypes associated with transmission Prof. dr. G. Lindahl – Role of M protein Career development workshops   Prof. dr. G. Pasterkamp – Innovation and valorization CLS services – Applying for a job is fun!


Prof. dr. Carl G. Figdor Dep. of Tumor Immunology, Radboud UMC Nijmegen, The Netherlands Dendritic cells in cancer-immunotherapy: ‘Next steps to take’ Vaccination is the most effective way of protection against micro-organisms. No wonder that immunologists spend great effort to exploit vaccination to fight devastating disease like cancer. The main problem is that cancerous cells are much alike normal cells, making development of effective vaccines extremely difficult. In addition to cancer cell derived or synthetic vaccines, Dendritic Cell (DC)based immunotherapy is explored worldwide in clinical vaccination trials with cancer patients. In my presentation I will provide insight in the state of the art and novel directions to design even more effective vaccines. I will present the first results of vaccination trials with specific subsets of DC and show that these cells are extremely potent in initiating immune responses in cancer patients. I will discuss the future perspective of DC based cancer immunotherapy, also in view of the recent introduction of immune checkpoint inhibitors in the clinic and the need for biomarkers that may predict which patients might benefit most from immunotherapy. Prof. dr. Figdor obtained his Master’s degree in 1979 from the University of Utrecht and his PhD degree in 1982 from the University of Amsterdam working at the Netherlands Cancer Institute (NKI). At the Netherlands Cancer Institute he got tenured in 1985 and started his own research group on Tumor Immunology. In 1992 Carl Figdor became Professor in Cell Biophysics at the University of Twente, and in 1994 he moved to the Radboud University Medical Centre Nijmegen to start a new department on Tumor Immunology as a Professor in Immunology. Here he initiated a large translational program exploiting the immune system to fight cancer. From 2001 – 2011 he worked as the first scientific director of the Nijmegen Centre for Molecular Life Sciences (NCMLS), in which his department is currently located. Carl Figdor is a member of the Royal Netherlands Academy of Arts and Sciences (KNAW) since 2008 and is the recipient of several awards, including the Dutch Spinoza Award in 2006, and the KWO award from the Dutch Cancer Society in 2009.He obtained an ERC Advanced Investigator grant in 2011. Prof. dr. Gunnar Lindahl Dept. of Laboratory Medicine, Lund University, Lund, Sweden Escape from innate and adaptive immunity by Streptococcus pyogenes: role of M protein. The Gram-positive bacterium Streptococcus pyogenes (group A streptococcus) is one of the most common human pathogens. The most extensively studied virulence factor of this pathogen is M protein, identified by Lancefield in 1928 and the first bacterial surface protein implicated in virulence. Importantly, M protein of different S. pyogenes strains varies in sequence, in particular in the N-terminal hypervariable region (HVR), allowing clinical isolates to be divided into about 200 M types. Classical work showed that M protein confers resistance to phagocytosis. Thus, M protein plays an essential role in evasion of innate immunity. All available evidence indicates that phagocytosis resistance results from ability of the M protein to block deposition of complement on the bacterial surface. The mechanism involves ‘hijacking’ of at least one human plasma protein to the surface-bound M protein. In particular, many M proteins hijack human fibrinogen or the complement inhibitor C4BP to block complement deposition. The key role of M protein in virulence makes it a major target for protective antibodies, which are mainly directed against the N-terminal HVR and are type-specific. But what is the function of the HVR, making it a target for protective antibodies? We have devoted much work to this problem, because hypervariability is a phenomenon of major importance in microbiology and immunology, making it of considerable interest to understand it at a molecular level. Our data indicate that most, and possibly all, M protein HVRs bind a human plasma protein, a property that is retained in spite of the extreme sequence divergence. In particular, many HVRs bind the complement inhibitor C4BP, which is implicated in phagocytosis resistance. Moreover, some HVRs bind the complement regulator factor H, which unexpectedly does not confer phagocytosis resistance, emphasizing the difficulty in understanding the role of a bound human protein. Our recent work indicates that the HVR of an M protein escapes antibodies not only through sequence variability but also through a second mechanism. While the HVR is generally assumed to be under strong selective pressure and to elicit a strong immune response, we made the paradoxical finding that the HVR is weakly immunogenic. Apparently, the function of the HVR is so important, that S. pyogenes has evolved two mechanisms to evade antibodies to this region in M protein: sequence variability and weak immunogenicity. Work is in progress to identify the molecular basis for the weak anti-HVR response. Weak immunogenicity may be an underestimated mechanism of immune evasion that could be of general importance. Dr. Thijn R. Brummelkamp Groupleader at Dutch Cancer Society (NKI/AVL) Amsterdam, The Netherlands Haploid genetic cell screening in host-pathogen biology. A powerful and direct way to gain insight into complex biological systems is to remove individual components and observe the consequences. By doing so, genetics has revolutionized many aspects of biology. Although human cell cultures are often used as experimental tool, genetics in cultured cells has lagged behind due to technical limitations. Our group has developed an entirely novel genetic model system based on insertional mutagenesis- in haploid and near-haploid human cells. We have shown that this approach enables the generation of knockouts for most human genes and can be used to pinpoint genes that are involved in phenotypes of interest. Combined with next-generation sequencing approaches, this method generates high-density genetic overviews of genes required for nearly any selectable cell trait. In a variety of genetic screens we have identified host factors required for infection of cells by influenza virus, the first entry receptor for a Clostridium difficile toxin and we identified the cholesterol transporter NPC1 as the long-sought intracellular entry receptor for Ebola virus. In this presentation I will highlight the power of this screening approach and describe our recent insights into host-pathogen biology. For his studies Thijn Brummelkamp received the Antoni van Leeuwenhoek Award (2003), The Annual NVBMB Award (2004, Dutch Association for Biochemistry and Molecular Biology), he was chosen as one of the world’s top 35 Young Innovators by MIT’s Technology Review Magazine (2005) and received the Kimmel Scholar Award (2006). He received an ERC starting grant from the European Research Council (2012), the 2012 Molecular Biosystems Early Career Award and the EMBO Gold Medal 2013. Prof. dr. William (Bill) A. Paxton Dep. Clinical Infection, Microbiology and Immunology, University of Liverpool, UK CCR5 and HIV-1 resistance Paxton’s lab focusses on the better understanding of host as well as viral factors associated with either risk of HIV-1 infection or rate of disease progression. Understanding these, will potentially lead to the development of new products and strategies aimed at curtailing transmission or slowing disease progression. Over the years a number of host molecules with the potential to modulate HIV-1 transmission have been identified, including the CCR5 co-receptor, bile-salt stimulated lipase (BSSL) from human milk and MUC6 from seminal plasma. Genetic polymorphisms within the genes coding for CCR5 and BSSL have also been associated with HIV-1 transmission and disease course. Also the demonstrated interaction of HIV-1 with dendritic cells can provide a mechanism of immune evasion where antibody neutralized virus can be rendered newly infectious. In the last year Paxton’s group has published that high levels of neutralizing antibodies in HIV-1 infected mothers can associate with a heightened risk of mother to child transmission in utero, with implications for HIV-1 vaccine development. His talk will focus on the identification of the CCR5 co-receptor for HIV-1 and the identification of a deletion in CCR5 leading to HIV-1 resistance. Bill Paxton undertook his PhD studies at the Imperial College of Science Technology and Medicine, University of London, on the characterization of immune responses against specific antigens from the filarial nematode Brugia Malayi, the causative agent of elephantiasis. He spent his postdoctoral research years at the Aaron Diamond AIDS Research Center, Rockefeller University, New York, where he was involved with the identification that a deletion in the CCR5 chemokine receptor can provide a high level of protection against HIV-1 transmission and disease progression. His Assistant and Associate professor years were spent at the University of Amsterdam, the Netherlands, where he focussed on further characterising host and viral factors associated with HIV-1 infection. Currently he holds a professorship chair at the University of Liverpool, UK, where the lab focuses on HIV-1 and more so in the context of co-pathogen infections. Dr. Leila Perié Utrecht Center for Quantitative Immunology, Utrecht University, The Netherlands. Deciphering the hematopoietic pathway at the single cell level: results from cellular barcoding. Cellular barcoding is a powerful experimental technique that simultaneously traces the in vivo differentiation of individual cells. Using cellular barcoding combined with mathematical modeling, we traced the progeny of hematopoietic progenitors and reconstituted the relationship between cell lineages with single cell resolution. We showed that individual lymphoid-primed multi-potent progenitors (LMPPs) are generally not multi-outcome; instead, they produce heterogeneous patterns of limited types of blood cells (Naik S, Perié L et al, Nature 2013). Interestingly, we found that many LMPPs produce several types of dendritic cells without producing any lymphoid and myeloid cells. We then developed a new mathematical framework to infer the nature of the hematopoietic tree (Perié L et al, Cell Reports, 2014). With this approach, we showed that the classical model of hematopoiesis cannot explain our data and that the hematopoietic pathway requires additional branches beyond those found in the classical model, leading us to propose a revised model. In this revised model, hematopoietic differentiation follows a mechanism of loss of potential that is equal at every step of differentiation (Ogawa et al., 1983, Tsuji and Nakahata, 1989). In particular, dendritic cells seem to branch directly from the multi-potent progenitors in addition to the already known lymphoid and myeloid branches. Dr. L. Perié has been awarded with the Young Researcher Price by the Bettencourt Schuler Foundation (September 2010), an Intra-European Postdoctoral Marie Curie fellowship (FP7)(April 2011) and recently received an ATIP-Avenir young PI starting grant from the french goverment (July 2014).

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