Annual report - GHI 2015-16 by EPFL School of Life Sciences

GHI

Global Health Institute Since its foundation in 2006, the Global Health Institute (GHI) has contributed to the understanding, diagnosis, prevention and treatment of infectious diseases, which account for half of the deaths in the developing world and claim 18 million human lives every year. The GHI is comprised of 10 groups, all engaged in different facets of research linked to human health but with strong emphasis on diseases of truly global importance such as HIV/AIDS and tuberculosis. The current workforce comprises ~120 students, postdoctoral-fellows, technicians and scientists, representing more than 25 different nations. The research portfolio at the GHI includes a balanced mixture of basic and translational work. Mechanisms of host-pathogen interactions and innate and acquired immunity against disease are being studied using multidisciplinary approaches. A unique feature of the GHI is its ability to tackle crucial world health issues by harnessing cutting edge technologies developed elsewhere at EPFL to underpin research on diagnostics, drugs and vaccines as well as disease mechanisms. Prominent amongst these are the nanotechnologies, micro-engineering and bioinformatics. Aware of the impact of the microbiota on human health, the GHI is actively developing new programs in this area and in digital epidemiology. http://sv.epfl.ch/GHI

Stewart Cole - Director

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Ablasser Lab Andrea Ablasser -Tenure-Track Assistant Professor

After graduating in medicine at the University of Munich, Germany in 2008, Andrea Ablasser moved to the University of Bonn to do her post-doctoral research which focused on understanding innate nucleic acid sensing mechanism that lead to an antiviral immune response. In 2014, the Ablasser lab was opened as part of the Global Health Institute in the School of Life Sciences of the EPFL.

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ablasserlab.epfl.ch

Introduction

Results Obtained

The sensing of foreign DNA is crucial for host defense against several pathogens. In the cytosol the enzyme cyclic GMP-AMP synthase (cGAS) is critical for the recognition of pathogen-derived DNA and provides key signals that initiate immune responses. Recently, we have shown that cGAS is an innate sensor for Mycobacterium tuberculosis. Beyond infection accumulating evidence indicates that cGAS is also active during autoimmune diseases and controls immune responses that underlie cancer immunosurveillance, which form the basis of our current research efforts.

Recently we have shown that cGAS is an essential for the innate recognition of Mycobacterium tuberculosis by macrophages.

Keywords Innate immunity, nucleic acid sensing, type I interferons.

GHI - Global Health Institute

Team Members Postdoctoral Fellows

Muhammet F. Gulen Baptiste Guey PhD Students

Simone Haag Sélène Glück Technicians

Nathalie Jordan Administrative Assistants

Valérie Pahud

cGAS-mediated signaling pathways Upon DNA sensing cGAS produces cGAMP, which activates STING to regulate de novo gene expression. STING-dependent signaling can also be activated by sensing cGAMP produced by neighboring cells and transferred through gap junctions or by recognition of cGAMP delivered in viral particles.

Selected Publications » Wassermann, R., Gulen, M.F., Sala, C., Garcia Perin, S., Lou, Y., Rybniker, J., Schmid-Burgk, J.L., Schmidt, T., Hornung, V., Cole, S.T. and Ablasser A. (2015) The ESX-1 secretion system of Mycobacterium tuberculosis differentially regulates cGAS- and inflammasome-dependent intracellular immune responses. Cell Host & Microbe 17(6): 799-810.

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Blokesch Lab Melanie Blokesch -Tenure-Track Assistant Professor

Melanie Blokesch studied biology at Ludwig-MaximiliansUniversity (LMU) in Munich, Germany. In 2004 she obtained her PhD degree with highest honor from the LMU Munich based on her work on bacterial hydrogen production and metalloenzyme maturation. From 2005 to 2009 she worked as a postdoctoral fellow at Stanford University (USA) before being appointed as tenure-track Assistant Professor (2009) and Associate Professor (2016) within the School of Life Sciences of EPFL.

blokesch-lab.epfl.ch

Introduction

Results Obtained

Our research focuses on the question “How and why do some bacteria evolve to become human pathogens?” Our model organism is Vibrio cholerae, the causative agent of cholera. Cholera is still widespread around the world with up to 4 million cases every year. The ultimate goal of our research is to link the ecology and evolution of the organism to the epidemiology of the disease. V. cholerae is a normal member of aquatic habitats and is often found associated with zooplankton. Under such growth conditions, V. cholerae induces a developmental program known as natural competence for transformation. Natural competence allows the bacterium to take up free DNA from the environment and to recombine this genetic material into its own genome. As a consequence, natural competence fosters horizontal gene transfer in bacteria and contributes to the spread of antibiotic resistance genes and virulence traits. Our previous work deciphered the regulatory circuits that drive natural competence in this organism and the molecular mechanism of the DNA uptake process. We also demonstrated that the type VI secretion system (T6SS) is part of the natural competence regulon, and as such, its production is induced by chitinous surfaces. The T6SS is a molecular weapon that is considered a virulence factor in many Gram-negative pathogens. As a consequence, chitininduced V. cholerae kill neighboring bacteria and absorb the released DNA via their DNA-uptake machinery, which contributes to the diversification of the pathogen’s genes and thus to its evolution. Apart from these topics, we are also interested in the interaction of V. cholerae with environmental hosts and the role that virulence factors play in this context. We suggest that predation is a driving force behind the evolution of pathogenicity in V. cholerae.

Killing for DNA: The type VI secretion system of Vibrio cholerae fosters horizontal gene transfer V. cholerae is considered an important model organism for elucidating virulence regulation. In this context, the involvement of bacterial cell-tocell communication known as quorum sensing (QS) has been extensively studied. More recently, researchers also became interested in the contribution of a molecular killing device, the type VI secretion system (T6SS), towards pathogenesis. However, much less is known about the bacterium’s environmental lifestyle, where it often associates with the carbon-rich chitinous surfaces (see Figure) and where it has to compete with other bacteria. We showed that growth on such chitinous surfaces triggers the production of the T6SS, which enhances horizontal gene transfer by deliberate killing of neighboring bacteria followed by the absorption up of their DNA. V. cholerae establishes a replication niche within free-living amoebae A driving force behind the evolution of pathogenic bacteria is predation. Current hypotheses suggest that virulence mechanisms might reflect immediate adaptations to predation in natural environments. We therefore investigated the interaction of V. cholerae with a co-habiting aquatic amoeba, Acanthamoeba castellanii, at the single-cell level. We observed that a subset of V. cholerae bacteria is capable of resisting digestion by A. castellanii; moreover, the undigested bacteria were either exocytosed by the amoebae or established a replication niche within the osmoregulatory organ of the amoeba. In the latter case, efficient growth of the bacteria occured within A. castellanii. Ultimately, V. cholerae returned to its aquatic habitat through lysis of the amoeba. This study therefore describes a new host-pathogen interaction for V. cholerae.

Keywords Horizontal gene transfer, evolution of pathogens, bacterial communities, regulatory networks, cholera.

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GHI - Global Health Institute

Team Members Postdoctoral Fellows

David Adams Milena Jaskólska Lisa Metzger Charles Van der Henst PhD Students

Natália Drebes Dörr Noémie Matthey Technicians

Sandrine Stutzmann Candice Stoudmann Julien Chambaud (apprentice) Bioinformatician

Anne-Catherine Portmann Administrative Assistants

Marisa Marciano Wynn

In its natural habitat, the human pathogen Vibrio cholerae colonizes chitinous surfaces as shown in this SEM image. Such colonization fosters close contact between bacteria, which enhances the transfer of genetic material by means of horizontal gene transfer. Image credit: M. Blokesch & G. Knott.

Selected Publications » Metzger, L.C., Stutzmann, S., Scrignari, T., Van der Henst, C., Matthey, N. and Blokesch, M. (2016) Independent regulation of type VI secretion in Vibrio cholerae by TfoX and TfoY. Cell Rep. 15:951-958. » Stutzmann, S. and Blokesch, M. (2016) Circulation of a quorum-sensing-impaired variant of Vibrio cholerae strain C6706 masks important phenotypes. mSphere 1:e000098-16. » » » » »

Matthey, N. and Blokesch, M. (2016) The DNA Uptake Process of Naturally Competent Vibrio cholerae. Trends Microbiol. 24:98-110. Van der Henst, C., Scrignari, T., Maclachlan, C. and Blokesch, M. (2016) An intracellular replication niche for Vibrio cholerae in the amoeba Acanthamoeba castellanii. ISME J. 10:897-910. Metzger, L.C. and Blokesch, M. (2016) Regulation of competence-mediated horizontal gene transfer in the natural habitat of Vibrio cholerae. Curr. Opin. Microbiol. 30:1-7. Blokesch, M. (2015) Competence-induced type VI secretion might foster intestinal colonization by Vibrio cholerae. BioEssays 37:1163-1168. Borgeaud, S., Metzger, L.C., Scrignari, T. and Blokesch, M. (2015) The type VI secretion system of Vibrio cholerae fosters horizontal gene transfer. Science 347:63-67.

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Cole Lab Stewart T. Cole - Full Professor - Director of the Global Health Institute (GHI)

Professor Stewart Cole is an internationally acclaimed authority on the pathogenicity, drug resistance, evolution and genomics of the tubercle and leprosy bacilli. His laboratory is currently focused on discovering new drugs to treat tuberculosis. The findings of his research are of direct relevance to public health and disease-control in both the developing world and the industrialized nations. He has published over 300 scientific articles and been honored by many professional prizes, decorations and awards.

cole-lab.epfl.ch

Introduction

Results Obtained

UPCOL uses a multidisciplinary approach to tackle global health problems such as tuberculosis (TB), Buruli ulcer and leprosy. Using screening and genome biology as platforms we are actively involved in discovering new drugs to treat TB and other mycobacterial diseases. To date, we have discovered many interesting leads for development including the natural product, pyridomycin, the thienopyrimidines, the carboxyquinoxalines, the quinazolines and, above all, the benzothiazinone (BTZ) series. The latter gave rise to PBTZ169, a highly potent drug candidate that irreversibly inhibits an essential enzyme called DprE1, which plays a critical role in the biogenesis of the mycobacterial cell wall. The preclinical development of PBTZ169 was undertaken by the not-for-profit foundation Innovative Medicines for Tuberculosis (iM4TB), an EPFL spin-off. In 2017, iM4TB will supervise the first clinical trials of PBTZ169 to be held in Switzerland.

TB Drug Discovery Among our most notable achievements were taking the BTZ drugs from discovery to the clinic. We have also shown that PBTZ169 is compatible with all leading TB drugs and drug candidates and thus has the potential for inclusion in a new combination therapy. PBTZ169 is currently in phase 2 clinical trials in Russia. We are now developing an antivirulence approach to drug discovery by inhibiting the ESX-1 system.

Keywords Tuberculosis, leprosy, drug discovery, pathogenesis.

Protein secretion and pathogenicity The ESX-1 secretion system, the major virulence determinant of M. tuberculosis, exports small helical-hairpin proteins from the ESAT-6 family as well as other effector proteins of unknown function. We are using an integrated approach to elucidate the organization, architecture, structure and function of this ATPdriven secretory apparatus. We recently showed that the EspC component forms a filamentous structure in the cell envelope and could serve as a needle or a piston for protein export. A regulatory map of the M. tuberculosis genome We are studying gene regulation by using chromatin-immunoprecipitation of DNA-binding proteins in conjunction with high-throughput sequencing to localize the various binding sites along the genome. All the RNA polymerase, NusA, PhoP and EspR binding sites were mapped in two different strains in two different growth phases and the role of several nucleoid-associated proteins, including H-NS and mIHF, was investigated. Phylogeography of leprosy Leprosy remains a serious public health problem. We have developed an epidemiological tool that employs whole genome sequence (WGS) analysis of M. leprae, to monitor transmission of the disease and have used this to retrace the spread of leprosy and to explore animal reservoirs. By this means we showed that red squirrels in the UK are naturally infected with M. leprae. Together with the WHO, we are also monitoring the emergence of drug resistance worldwide using WGS and skin biopsies.

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GHI - Global Health Institute

Team Members Postdoctoral Fellows

Andrej Benjak Andréanne Lupien Jérémie Piton Florence Pojer Claudia Sala Rita Székely PhD Students

Charlotte Avanzi Shi-Yan Caroline Foo Nina Odermatt Paloma Arnedo Soler Raphael Sommer Lou Ye Master’s Students

Chloé Loiseau Technicians

Stefanie Boy-Röttiger Philippe Busso Anthony Vocat A red squirrel with signs of leprosy on its ear.

Administrative Assistants

Cécile Prébandier

Selected Publications » Lou, Y., Rybniker, J., Sala, C. and Cole, S.T. (2017) EspC forms a filamentous structure in the cell envelope of Mycobacterium tuberculosis and impacts ESX-1 secretion. Mol Microbiol. 103: 26-38. » Piton, J., Foo, C.S. and Cole, S.T. (2017) Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors. Drug Discovery Today 22:526-533

» Foo, C. S., Lechartier, B., Kolly, G.S., Boy-Rottger, S., Neres, J., Rybniker, J., Lupien, A., Sala, C., Piton, J. and Cole, S.T. (2016) Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis. Antimicrobial Agents Chemother. 60: 6451-6459. » Cole, S.T. (2016) Inhibiting Mycobacterium tuberculosis within and without. Philos Trans R Soc Lond B Biol Sci. 371: pii 20150506. » Benjak, A., Uplekar, S., Zhang, M.,Piton, J., Cole, S.T. and Sala, C. (2016) Genomic and transcriptomic analysis of the streptomycin-dependent Mycobacterium tuberculosis strain 18b. BMC Genomics 17: 190. » Avanzi, C., Del-Pozo, J., Benjak, A., Stevenson, K., Simpson, V.R., Busso, P., McLuckie, J., Loiseau, C., Lawton, C., Schoening, J., Shaw, D.J., Piton,J., Vera-Cabrera, L., Velarde-Felix, J.S., McDermott, F., Gordon, S.V., Cole, S.T. and Meredith, A.L. (2016) Red squirrels in the British Isles are infected with leprosy bacilli. Science 354: 744-747.

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Fellay Lab Jacques Fellay - SNF Professor

Jacques Fellay is a medical scientist with expertise in infectious diseases and human genomics. He obtained an MD from the University of Lausanne and a PhD form University of Utrecht. Jacques Fellay joined the EPFL in April 2011 as an SNSF Professor; he is also a Group Leader at the Swiss Institute of Bioinformatics and a Visiting Physician at the Service of Infectious Diseases of the CHUV in Lausanne.

fellay-lab.epfl.ch

Introduction

Results Obtained

Research in the Fellay lab focuses on human genomics of infection and immunity. We explore the genetic roots of inter-individual differences in response to various infectious diseases, with a particular emphasis on genomic interactions between pathogens and their human hosts. At the crossroad between basic science and the clinical world, we are committed to translational genomic research, aiming at identifying, validating and bringing to clinical use genetic markers of susceptibility to infectious diseases.

During the two past years, our lab has focused its research on four synergistic areas.

We use a combination of genomic technologies, bioinformatic analyses and functional studies to understand the most severe clinical presentations of common infections (including diseases caused by respiratory viruses, Hepatitis B virus, HIV, group B Streptococcus, and others), and the impact of host genetic diversity on intra-host pathogen evolution. Methods include genomewide genotyping and association analysis, exome/genome sequencing and transcriptomics. We also collaborate with colleagues from the EPFL IC faculty to develop innovative solutions for genomic privacy, an essential trust-building component on to road toward genomic-based medicine.

Keywords Human genomics, infectious diseases, host-pathogen interactions, deepsequencing, translational genomics, genomic privacy, personalized medicine

We first used genome-wide genotyping and imputation, association analysis and in-depth dissection of signals present in the HLA region to delineate the impact of common human genetic variation on multiple phenotypes, including spontaneous HIV control (McLaren et al. 2015); immune activation and microbial translocation during chronic HIV infection (Perkins et al. 2015); and humoral response to common viruses (Hammer et al. 2015). Second, we investigated the influence of rare genetic variants on several infectious diseases using exome and RNA sequencing of carefully selected and thoroughly characterized clinical cases. The strategy has been applied to children suffering from severe respiratory symptoms due to common viruses; to liver transplant recipients who developed fulminant hepatitis upon infection with HBV; and to neonates with bacterial sepsis in the absence of any comorbidity (Asgari et al. 2016). Potentially causal genetic variants are validated genetically and then followed up functionally. A third line of research is the joint of human and viral genomes (described in Bartha et al. eLife 2013). We expanded this “genome-to-genome” strategy to integrate intra-host genetic diversity of chronic viruses, and to use it for bacterial pathogens. This pioneering work allowed us to start several academic and industrial collaborations. Finally, we also continued our work on genomic privacy in strong collaboration with the group of Prof. J.P. Hubaux (EPFL IC). In particular, we contributed to the first utilization of homomorphic encryption in the clinical setting, by running a pilot genomic study in collaboration with the seven outpatient clinics of the Swiss HIV Cohort Study. We demonstrated that it is feasible to ensure both patient privacy and usability of human genetic data in the context of HIV treatment (McLaren et al. 2016).

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GHI - Global Health Institute

Team Members Postdoctoral Fellows

Christian Hammer Nimisha Chaturvedi Alessandro Borghesi Thomas Junier Samira Asgari PhD Students

Petar Scepanovic Christian Thorball Olivier Naret Master’s Students

Flavia Hodel

Administrative Assistants

Marisa Marciano Wynn

Five amino acid positions in the ( ) -B and (B) - proteins significantly associate with HIV viral load. They all line the HLA peptide-binding groove and explain the majority of the genome-wide association signal. (C) Effect on viral load of individual amino acid residues at each position.

Selected Publications » McLaren, P.J., Coulonges, C., Bartha, I., Lenz, T.L., Deutsch, A.J., et al. (2015) Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load. PNAS 112(47):14658-14663. » Bartha, I., Rausell, A., McLaren, P.J., Mohammadi, P., Tardaguila, M., et al. (2015) The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome. PLoS Computational Biology 11(12):e1004647. » Hammer, C., Begemann, M., McLaren, P.J., Bartha, I., Michel, A., et al. (2015) Amino acid variation in HLA class II proteins is a major determinant of humoral response to common viruses. American Journal of

Human Genetics 97(5):738-743. » Perkins, M., Bartha, I., Timmer, K., Liebner, J.C., Wollinsky, D., et al. (2015) The interplay between host genetic variation, viral replication and microbial translocation in untreated HIV-infected individuals. Journal of Infectious Diseases 212(4):578-584. » Rusert, P., Kouyos, R.D., Kadelka, C., Ebner, H., Schanz, M., et al. (2016.) Determinants of HIV-1 broadly neutralizing antibody induction. Nature Medicine 22(11):1260-1267. » Asgari, S., McLaren, P.J., Peake, J., Wong, M., Wong, R., et al. (2016). Exome sequencing reveals primary immunodeficiencies in children with community-acquired pseudomonas aeruginosa sepsis. Frontiers in Immunology 7:357. » McLaren, P.J., Raisaro, J.L., Aouri, M., Rotger, M., Ayday, E., et al. (2016)Privacy-preserving genomic testing in the clinic - a model using HIV treatment. Genetics in Medicine 18(8):814-822.

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Harris Lab Nicola Harris - Associate Professor

NNicola Harris was born and completed her PhD thesis in New Zealand. In 2002 she moved to ZĂźrich, Switzerland as a postdoctoral fellow in the lab of Hans Hengartner and the Nobel Laureate Rolf Zinkernagel. In July 2005 she joined the ETH Zurich as an Assistant Professor and in August 2009 she moved to the Global Health Institute, Faculty of Life Sciences, EPFL.

harris-lab.epfl.ch

Introduction

Results Obtained

The intestinal mucosa represents an extensive interface between the body and the external environment that is constantly exposed to environmental microorganisms. Amongst these intestinal bacteria are present in vast numbers (1012 per gram of intestinal contents) in all individuals at all times. Worms (helminths) can also establish chronic infections within our intestines and were present in a near ubiquitous manner throughout mammalian evolution. Today intestinal helminths still infect approximately 1/3 of the worldâ&#x20AC;&#x2122;s population, with the heaviest infections found in children living in poor communities within developing countries.

Type 2 immunity and protection against helminths: In the past few years we have expanded on our findings that immune antibodies limit helminth infection by showing that these small proteins function by activating immune cells called phagocytes (or macrophages) to attach to and paralyze these large multicellular parasites. We also identified the antibody isotypes and host receptors involved in this response and found a very surprisingly role for antibodies normally associated with bacterial but not helminth infection. We then expanded on these studies to show that antibodies directed against helminths also functioned to activate the macrophages to release soluble factors that promoted wound repair. Lastly we investigated the factors regulating antibody production and uncovered a role type 2 immune responses in promoting the remodelling of lymphoid organs to allow new B cell rich follicles to form which support antibody production. This remodelling involved a previously unknown interaction between B cells and stromal cells within the lymphoid tissues.

Our work aims to investigate how type 2 immunity limits the number of helminths able to establish long-term infection in the intestine and how it also promotes wound repair following the migration of helminth larvae through tissues. We are also actively investigating how low burdens of intestinal helminths can actually improve health by limiting the development of chronic inflammatory disease (allergy and autoimmunity) and protecting against excessive weight gain (obesity). With regard to this latter aim we are performing detailed studies of how helminth infection impacts on bacterial communities within the intestine to modulate both the species present and their production of health promoting metabolites.

Keywords Intestinal helminths, intestinal bacteria, type 2 immunity, allergy, obesity

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Helminth-bacterial interactions and the modulation of allergy: In a separate project we investigated whether helminths impact on the rich and complex community of bacteria within the intestine. We were able to demonstrate that helminth infection altered intestinal bacterial communities to promote the production of small metabolites, called short chain fatty acids (SCFA) which promoted the expansion of a specialized subset of immune cells that functioned to limit inflammation and reduce the severity of allergy asthma. This work uncovered a previously unrecognized role for the microbiota in helminth-induced modulation of host immunity and identified one of the molecular pathways involved in this regulation. Such insight should prove useful for the design of preventative and therapeutic treatment of allergies using microbial compounds. We are now expanding this work to include studies of obesity.

GHI - Global Health Institute

Team Members Postdoctoral Fellows

Tiffany Bouchery Lalit Kumer Dubey Mati Moyet PhD Students

Luc Lebon Alexis Rapin Kathleen Shah Beatrice Volpe Technicians

Manuel Kulagin Audry Chuat Administrative Assistants

Dagmara Dylong

n amed lymph node he picture shows the draining lymph node of an animal with (right panel) or without (left panel) intestinal helminthes. Green areas show follicles containing B cells that produce antibodies and protect the animals against further infection. Red areas show adjacent T cells.

Selected Publications » Harris, N. (2016) Immunology: The enigmatic tuft cell in immunity. Science 351:1264-1265. » Kumar Dubey, L., Lebon, L., Mosconi, I., Ying Yang, C., Scandella, E., Ludewig, B., Luther, S. and Harris, N.L. (2016) Lymphotoxin-dependent B 1 cell-FRC crosstalk promotes de novo follicle formation and antibody production following intestinal helminth infection. Cell Reports 15:1527-1541. » Zaiss, M., Rapin, A., Lebon, L., Dubey, L.K., Mosconi, I., Sarter, K., Piersigili, A., Menin, L., Walker, A. W., Rougemont, J., Paerewijck, O., Geldhof, P., McCoy, K.D., Macpherons, A.J., Croese, J., Giacomin, P.R., Loukas, A., Junt, T., Marsland, B.J. and Harris, N.L. (2015) The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation. Immunity 43:998–1010. » Harris, N. (2015) Immunology: Chronic effects of acute infections. Nature 526:509-510.

» Mosconi, I., Dubey, L.K., Volpe, B., Esser-Von Bieren, J., Zaiss, M.M., Lebon, L., Massacand, J.C. and Harris, N. (2015) Parasite proximity drives the expansion of regulatory T cells in Peyer’s Patches following intestinal helminth infection. Infection and Immunity 83: 3657-3665. » Esser-von Bieren, J., Volpe, B., Sutherland, D.B., Bürgi, J., Verbeek, J.S., Marsland, B.J., Urban, J.F. and Harris, N. (2015) Immune antibodies and helminth products drive CXCR2-dependent macrophage-myofibroblast crosstalk to promote intestinal repair. PLoS Pathogens 11:e31004778. » Esser-von Bieren, J., Volpe, B., Kulagin, M., Sutherland, D.B., Guiet, R., Seitz, A., Marsland, B.J., Verbeek, J.S., and Harris, N.L. (2015) Antibody-mediated trapping of helminth larvae requires CD11b and Fc receptor I. J. Immunol. 194(3):1154-1163.

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Lemaitre Lab Bruno Lemaitre - Full Professor - Director of the Doctoral Program in Molecular Life Sciences (EDMS)

Bruno Lemaitre obtained his PhD in 1992 with Dario Coen at the University Pierre and Marie Curie (Paris) on the P element transposition in Drosophila. Next, he joined the laboratory of Jules Hoffmann (Strasbourg France) as a research associate where he began the genetic dissection of the Drosophila antimicrobial response. In 1998, he started his own laboratory on Drosophila immunity at the Centre Génétique Moléculaire (Gif-sur-Yvette, France). In 2007, he was appointed professor at EPFL.

lemaitrelab.epfl.ch

Introduction

Results Obtained

Our group uses Drosophila and a range of genetic tools to study physiology at the organismal level. The three main axes of our research are:

Our group uses Drosophila as a model to study physiological processes at the organismal level. We currently have three main axes of research focusing on:

1. 2. 3.

Drosophila innate immunity We are interested in the molecular mechanisms underlying phagocytosis, melanization, and encapsulation, three poorly characterized insect immune defense modules. Using single or combined mutations, we analyzed the individual function of three prophenoloxidases, enzymes involved in the melanization reaction. While a specific function can be assigned to each of the prophenoloxidases, knocking out two out of the three genes is required to abolish melanization. An ambitious project to systematically delete all the immunity-related genes is currently in progress.

Drosophila immunity Drosophila-Spiroplasma interaction Drosophila gut function (including mucosal immunology, epithelium renewal, and metabolism)

Our research provides insights into basic biological phenomenon, which are often conserved in humans. They also increase our knowledge about physiology in insects, some of which are vectors of human and plant diseases as well as crop pests.

Keywords Innate immunity, gut homeostasis, host-pathogen interactions, Drosophila, Symbiosis

The Drosophila-Spiroplasma interaction Virtually every insect species harbors facultative bacterial endosymbionts (e.g. Wolbachia etc.) that are transmitted in females to their offspring. In spite of the growing interest in endosymbiosis, very little is known about the molecular mechanisms underlying most endosymbiont-insect interactions. Our laboratory analyses the interaction between Drosophila and its endosymbiont Spiroplasma poulsonii. We have recently shown showed that the growth of Spiroplasma is not controlled by the immune system but by the availability of lipid. This dependence on lipid couples Spiroplasma growth to the nutritional state of its host. In 2015, we also provided the first genome of an endosymbiotic Spiroplasma: S. poulsonii. The digestive tract: an interactive barrier Apart from its central role in digesting and absorbing nutrients, the inner surface of the digestive tract also serves as the first line of defense against a wide variety of pathogens. Using an integrated approach, we are studying the mechanisms that make the gut an efficient and interactive barrier. We have recently characterized the role of the transcription factor Sox21a in intestinal stem cell differentiation, and articulate how a differentiation defect can lead to tumor formation (See Figure). In 2014, we described a new role for the TGFß signaling in the regulation of sugar homeostasis and digestive enzyme expression.

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GHI - Global Health Institute

Team Members Postdoctoral Fellows

Anna Dostalova Igor Iatsenko Juan Paredes Elodie Ramond Samuel Rommelaere Zongzhao Zhai Toshiyuki Harumoto Xiaoxue Li PhD Students

Jan Dudzic Gonzalo Arraez Technicians

Jean-Philippe Boquete Fanny Schüpfer Christophe Remondeulaz Administrative Assistants

Véronique Dijkstra

Intestinal progenitor tumor in the adult Drosophila midgut. confocal section of progenitor tumor in the adult midgut of a ox2 a mutant y. Nuclei are stained in blue, visceral muscle surrounding the intestine and brush border of enterocytes are in red, and the tracheal system in green (From Zhao 2015).

Selected Publications » Zhai, Z., Kondo, S., Ha, N., Boquete, J.P., Brunner, M., Ueda, R. and Lemaitre, B. (2015) Accumulation of differentiating intestinal stem cell progenies drives tumorigenesis. Nat Commun. 6:10219. » Chakrabarti, S., Dudzic, J.P., Li, X., Collas, E.J., Boquete, J.P. and Lemaitre, B. (2016) Remote control of intestinal stem cell activity by haemocytes in Drosophila. PLoS Genet. 12(5): e1006089.

Ramond, E., Maclachlan, C., Clerc-Rosset, S., Knott, G.W. and Lemaitre, B. (2016) Cell division by longitudinal scission in the insect endosymbiont Spiroplasma poulsonii. MBio. 7(4) pii: e00881-16. Paredes, J.C., Herren, J.K., Schüpfer, F. and Lemaitre, B. (2016) The role of lipid competition for endosymbiont-mediated protection against parasitoid wasps in Drosophila. MBio. 7(4) pii: e01006-16. Neyen, C., Runchel, C., Schüpfer, F., Meier, P. and Lemaitre, B. (2016) The regulatory isoform rPGRP-LC induces immune resolution via endosomal degradation of receptors. Nat Immunol. 17(10):1150-1158. Iatsenko, I., Kondo, S., Mengin-Lecreulx, D. and Lemaitre, B. (2016) PGRP-SD, an extracellular pattern-recognition receptor, enhances peptidoglycan-mediated activation of the Drosophila Imd pathway. Immunity 45(5):1013-1023. » Lemaitre, B. (2016) Connecting the obesity and the narcissism epidemics. Med Hypotheses 95:10-19. » » » »

133

McKinney Lab John McKinney - Full Professor - Director of the Doctoral Program in Biotechnology & Bioengineering (EDBB)

Prof. McKinney received his PhD from The Rockefeller University in 1994 for studies on eukaryotic cell cycle regulation. His postdoctoral studies at the Albert Einstein College of Medicine were focused on tuberculosis (1995-1998). Prof. McKinney headed the Laboratory of Infection Biology at Rockefeller University from 1999-2007. Since 2007, Prof. McKinney heads the Laboratory of Microbiology and Microsystems at EPFL. He is also the Section Director for Education in Life Sciences and Technology at EPFL.

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mckinney-lab.epfl.ch

Introduction

Results Obtained

Research in the McKinney lab is focused on understanding the mechanistic basis of microbial individuality, defined as cell-to-cell phenotypic variation that is not attributable to genetic or environmental differences. A deeper understanding of this phenomenon could lead to new strategies to eliminate subpopulations of bacteria that are refractory to antimicrobial therapy and host immunity. Our interdisciplinary research program comprises equal parts microbiology and microengineering. In particular, we design, develop, and apply new microfabricated tools for single-cell microbiology, combined with advanced imaging techniques based on optical and atomic force microscopy. All of our studies are focused at the single-cell level. Areas of biology that we study include: bacterial cell growth and division; bacterial metabolism; bacterial infection and immune evasion; bacterial antibiotic persistence and resistance; bacterial gene expression and phenotypic adaptation to stressful and fluctuating environments.

Genetically identical cells display metastable non-genetic variation in growth rates, gene expression, stress resistance, and other quantitative phenotypes. This phenotypic heterogeneity is critical for bacterial persistence in fluctuating environments because it ensures that some individuals will survive potentially lethal stresses that would otherwise extinguish the population. Our research focuses on the pathogenic organism Mycobacterium tuberculosis and uropathogenic Escherichia coli. We use time-lapse optical and atomic force microscopy and custom-made microdevices to study the real-time dynamics of bacterial behavior at the single-cell level.

Keywords Microbiology, microengineering, microfluidics, microbial microscopy

individuality,

In 2016 we reported that the carbon flux in mycobacteria is regulated by a rheostat-like mechanism (Murima et al. 2016 Nature Commun 7: 12527). We showed that this metabolite mediated allosteric regulatory circuit is responsible for maintaining a balance between energy production and precursor biosynthesis and thus represents a novel target for chemotherapy. In 2016 we reported the development of a microfluidic platform, InfectChip, to visualize host-microbe interactions and the different stages of infection at the single-cell level (Delince et al. 2016 Lab Chip 16: 3276-3285). We demonstrated the utility of this approach by using Dictyostelium discoideum as the host and Klebsiella pneumoniae and Mycobacterium marinum as model pathogens. In 2016 we conducted several studies to study the impact of novel antituberculosis pre-clinical compounds on Mycobacterium tuberculosis using our microfluidic microscopy approach (Martinez-Hoyos et al., 2016 EBioMedicine 8: 291-301; Batt et al., 2015 ACS Infect Dis 1: 615-626). These studies are not only useful for elucidating mode of action of the compounds but often are crucial for making Go/ No-Go decisions in terms of compound progression.

GHI - Global Health Institute

Team Members Senior Scientist

Neeraj Dhar

Postdoctoral Fellows

Alex Eskandarian Viveck Thacker Chiara Toniolo PhD Students

Matthieu Delincé Katrin Schneider Kunal Sharma Thomas Simonet Joëlle Ven Amanda Verpoorte Gaëlle Thurre Technicians

François Signorino-Gelo Schematic view of the InfectChip. The coverslip is patterned with thousands of chambers made of SU8. The snapshots on the right show timlapse images of Dictyostelium discoideum infected with uorescent ycobacterium marinum (red). From Delince et al., (20 ) ab hip 2 - 2 5.

Administrative Assistants

Suzanne Balharry

Selected Publications » Murima, P., Zimmermann, M., Chopra, T., Pojet, F., Fonti, G., Dal Peraro, M., Alonso, S., Sauer, U., Pethe, K. and McKinney, J.D. (2016) A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria. Nature Commun 7: 12527. » Tischler, A.D., Leistikow, R.L., Ramakrishnan, P., Voskuil, M.I. and McKinney, J.D. (2016) Mycobacterium tuberculosis phosphate uptake system component PstA2 is not required for gene regulation or virulence. PLoS One 11(8): e0161467. » Delincé, M.J., Bureau, J.B., López-Jiménez, A.T., Cosson, P., Soldati, T. and McKinney, J.D. (2016) A microfluidic cell-trapping device for single-cell tracking of host-microbe interactions. Lab Chip 16(17): 3276-3285. » Ramakrishnan, P., Aagesen, A., McKinney, J.D. and Tischler, A. (2016) Mycobacterium tuberculosis resists stress by regulating PE19 expression. Infect Immun 84(3): 735-746. » Martínez-Hoyos, M., Perez-Herran, E., Gulten, G., Encinas, L., Álvarez-Gómez, D., Alvarez, E., Ferrer-Bazaga, S., García-Pérez, A., Ortega, F., Angulo-Barturen, I., Rullas-Trincado, J., Blanco Ruano, D., Torres, P.,

Castañeda, P., Huss, S., Fernández Menéndez, R., González Del Valle, S., Ballell, L., Barros, D., Modha, S., Dhar, N., Signorino-Gelo, F., McKinney, J.D., García-Bustos, J.F., Lavandera, J.L., Sacchettini, J.C., Jimenez, M.S., Martín-Casabona, N., Castro-Pichel, J., Mendoza-Losana, A. (2016) Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor. EBioMedicine 8: 291-301. » Batt, S.M., Izquierdo, M.C., Pichel, J.C., Stubbs, C.J., Del Peral, L.V.G, Pérez-Herrán, E., Dhar, N., Mouzon, B., Rees, M., Hutchinson, J.P., Young, R.J., McKinney, J.D., Barros, D., Ballell, L., Besra, G.S. and Argyrou, A. (2015) Whole cell target engagement identifies novel inhibitors of Mycobacterium tuberculosis decaprenylphosphoryl-beta-D-ribose oxidase. ACS Infect Dis 1(12): 615-626. » Rullas, J., Dhar, N., McKinney, J.D., García-Pérez, A., Lelievre, J., Diacon, A.H., Hugonnet, J.E., Arthur, M., Angulo-Barturen, I., Barros-Aguirre, S. and Ballell, L. (2015) Combinations of beta-lactam antibiotics currently in clinical trials are efficacious in a DHP-1-deficient mice model of tuberculosis infection. Antimicrob Agents Chemother 59(8): 4997-4999.

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Salathé Lab Marcel Salathé - Associate Professor

Marcel Salathé is a digital epidemiologist working at the interface of population biology, computational sciences / engineering, and the social sciences. He received his PhD from ETH Zürich, and then went to Stanford University as a postdoc before becoming Assistant Professor at Penn States’ Center for Infectious Disease Dynamics. In August 2015, he returned to Switzerland as Associate Professor at EPFL.

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Introduction

Results Obtained

The Digital Epidemiology Lab is mainly dedicated to the production and analysis of new streams of digital data (big data) in order to improve public health, both locally and internationally. The group works on a variety of projects relating to human health or agricultural crops, and takes advantage of the latest technology to understand, describe or predict epidemics. One of its major projects, “PlantVillage”, is one of the largest libraries worldwide in terms of scientific knowledge on diseases of edible plants. It already lists 154 varieties and more than 1,800 diseases and continues to grow. “PlantVillage” is also a platform for dialogue and exchange among the best specialists and growers worldwide. Since last November, more than 50,000 images of healthy and infected plants were published and made freely accessible to allow experts in machine learning the development of algorithms able to immediately identify crop diseases. Our own group has applied deep learning models to reach an accuracy of over 99%. We have also recently developed an open data competition platform called crowdai.org.

Having arrived at EPFL in August 2015, most of the results obtained in 2015 were still flowing from research done at Penn State. The main findings related to pharmacovigilance, where we could show that Twitter can be used to identify adverse effects on HIV drug treatment, a finding that was published in the same year. Arriving at EPFL, I’ve spent the rest of the year setting up my lab at Campus Biotech in Geneva. We have started building a deep learning platform for the PlantVillage plant disease data, and have also begun the development of the open data challenge platform crowdAI.org. In addition, we’ve set up collaborative projects with the University Hospitals Zurich and Geneva, where we have started to studies measuring contact networks using wireless sensors. In 2016, we published our first paper on deep learning using the PlantVillage open dataset, demonstrating for the first time that plant diseases can be accurately diagnosed using artificial intelligence. We have run multiple challenges on the crowdAI platform, and have launched openfood.ch, the largest open food data base in Switzerland.

Keywords Digital epidemiology, health, disease, big data, machine learning, algorithms, AI, wireless sensors

GHI - Global Health Institute

Team Members Research Staff

Christopher Burger PhD Students

Gianrocco Lazzari Sharada Mohanty Martin Müller Technicians

Yannis Jaquet Sean Carroll Boris Conforty Trainee

Servan Grüniger Alberto Hernandez Administrative Assistants

Marina Secat

Visualization of activations in the initial layers of an AlexNet Deep Learning architecture demonstrating that a model has learnt to efficiently activate against diseased spots on an example leaf infected with Apple Cedar Rust.

Selected Publications » Vayena, E., Salathé, M., Madoff, L.C. and Brownstein, J.S. (2015) Ethical challenges of big data in public health. PLOS Computational Biology 11:e1003904. » » » » » »

Althaus, C.L. and Salathé, M. (2015) Measles vaccination coverage and cases among vaccinated persons. Emerging Infectious Diseases 21:1480-1481. Adrover, C., Bodnar, T., Huang, Z., Telenti, A. and Salathé, M. (2015) Identifying adverse effects of HIV drug treatment and associated sentiments using Twitter. JMIR Public Health and Surveillance 1:e7 Sun, X., Lu, Z., Zhang, X., Salathé, M and Cao, G. (2015) Targeted vaccination based on a wireless sensor system. Pervasive Computing and Communications (PerCom) Mohanty, S.P., Hughes, D.P. and Salathé, M. (2016) Using deep learning for image-based plant disease detection. Frontiers in Plant Science 7:1419. Salathé M. (2016) Digital pharmacovigilance and disease surveillance: combining traditional and big-data systems for better public health. Journal of Infectious Diseases 214: S399-S403. Wang, Z., Bauch, C.T., Bhattacharyya,S., d’Onofrio, A., Manfredi,P., Perc,M., et al. (2016) Statistical physics of vaccination. Physics Reports 664: 1-113.

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Trono Lab Didier Trono - Full Professor

After obtaining an M.D. from the University of Geneva and completing clinical training in pathology, internal medicine and infectious diseases in Geneva and at Massachusetts General Hospital, Didier Trono started a scientific career at the Whitehead Institute of MIT. In 1990, he joined the Salk Institute in San Diego to launch a center for AIDS research. Prof. Trono moved back to Europe seven years later, before taking the reins of the newly created EPFL School of Life Sciences, which he directed from 2004 to 2012. His research has long gravitated around interactions between viruses and their hosts and the development of tools for gene therapy. This led him to epigenetics, the current focus of his labâ&#x20AC;&#x2122;s investigation.

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Introduction

Results Obtained

Our laboratory has had a long-standing interest for interactions between viruses and their hosts. This led us in the past to study the biology of pathogens such as human immunodeficiency virus and hepatitis B virus, and to develop virus-based delivery systems for human gene therapy. Over the last twelve years, our research has shifted towards the field of epigenetics, to explore the impact of transposable elements and their controllers on transcriptional networks governing human biology. We have notably devoted much attention to the 350 KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor KAP1, which evolved during the last 400 million years from silencers of mobile genetic elements to master regulators of human development, physiology and evolution.

Transposable elements (TEs) may account for up to two-thirds of the human genome, and as genomic threats they are subjected to epigenetic control mechanisms engaged from the earliest stages of embryonic development. We previously determined that an important component of this process is the sequence-specific recognition of TEs by KRAB-containing zinc finger proteins (KRAB-ZFPs), a large family of tetrapod-restricted transcription factors that act by recruiting inducers of heterochromatin formation and DNA methylation. We further demonstrated that KRAB-ZFPs and their cofactor KAP1 exert a marked influence on the transcription dynamics of embryonic stem cells via their docking of repressor complexes at TE-contained regulatory sequences. It is generally held that, beyond this early embryonic period, TEs become permanently silenced, and that the evolutionary selection of KRAB-ZFPs and other TE controllers is the result of a simple evolutionary arms race between the host and these genetics invaders. Our analysis of the transcriptional activity of transposable elements in various developmental stages, tissues and cancers invalidates this dual assumption and demonstrates instead the potential of KRAB-ZFPs and their targeted transposon-based regulatory sequences as regulators of species-specific transcriptional networks governing human development and physiology. This field holds great promises to uncover new biomarkers and therapeutic targets for oncology and also opens new perspectives to explore human speciation.

Keywords Transposable elements, KRAB-ZFPs, epigenetics, stem cells, development, evolution

GHI - Global Health Institute

Team Members Post Doctoral Fellows

Marco Cassano Alberto De Iaco Marc Friedli Michaël Imbeault Suk Min Jang Julien Pontis Laia Simó Riudalbas Carmen Unzu Staff Scientist

Priscilla Turelli PhD Students

Natali Castro Diaz Andrea Coluccio Gabriela Ecco Pierre-Yves Helleboid Alexandra Iouranova Annamaria Kauzlaric Flavia Marzetta Technicians KZFPs and transposable elements interactions are foundations for species-specific transcriptional networks regulation. The complex interactions network between KZFPs (in grey) and TE families (in colors) are represented. Some KZFP / TE relationships are very exclusive (at the edge of the network), while some KZFPs recognize multiple families of TEs (for example SINEs and ERVs).

Selected Publications

Sandra Offner Charlène Raclot Sonia Verp Bioinformaticians

Evarist Planet Julien Duc Delphine Grun

Administrative Assistants

» Ecco, G., Cassano, M., Kauzlaric, A., Duc, J., Coluccio, A., Offner, S., Imbeault, M., Rowe, H.M., Turelli, P. & Trono, D. Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues. Dev Cell 36, 611-23 (2016).

Julia Prébandier Séverine Reynard

» Theunissen, T.W., Friedli, M., He, Y., Planet, E., O’Neil, R.C., Markoulaki, S., Pontis, J., Wang, H., Iouranova, A., Imbeault, M., Duc, J., Cohen, M.A., Wert, K.J., Castanon, R., Zhang, Z., Huang, Y., Nery, J.R., Drotar, J., Lungjangwa, T., Trono, D., Ecker, J.R. & Jaenisch, R. Molecular Criteria for Defining the Naive Human Pluripotent State. Cell Stem Cell 19, 502-515 (2016). Ecco, G., Rowe, H.M. & Trono, D. A Large-Scale Functional Screen to Identify Epigenetic Repressors of Retrotransposon Expression. Methods Mol Biol 1400, 403-17 (2016). Trono, D. Transposable Elements, Polydactyl Proteins, and the Genesis of Human-Specific Transcription Networks. Cold Spring Harb Symp Quant Biol 80, 281-8 (2015). Friedli, M. and Trono, D. (2015). The Developmental Control of Transposable Elements and the Evolution of Higher Species. Annu Rev Cell Dev Biol 31, 429-51 (2015). Singh, K., Cassano, M., Planet, E., Sebastian, S., Jang, S.M., Sohi, G., Faralli, H., Choi, J., Youn, H.D., Dilworth, F.J. & Trono, D. A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation. Genes Dev 29, 513-25 (2015). » Castro-Diaz, N., Friedli, M. and Trono, D. Drawing a fine line on endogenous retroelement activity. Mob Genet Elements. 5:1-6 (2015). » » » »

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Van der Goot Lab F. Gisou van der Goot - Full Professor - Dean of the School of Life Sciences

Introduction

Results Obtained

The general interest of our laboratory is to understand how biological membranes compartmentalize space, in 3D but also 2D, how shape is used to specify function, how transmission of information across membranes can be mediated. These overarching questions are addressed through the following main focuses:

Anthrax toxin receptors Through the study of biopsies from Hyaline Fibromatosis patients and of CMG2 knock out mice, combined with in vitro and tissue culture experiments, we found that CMG2 is a receptor for the extracellular matrix protein Collagen VI. CMG2 controls the extracellular levels of collagen VI. It does so by internalizing collagen VI into cells and targeting it for degradation in lysosomes. Upon loss of CMG2 function, collagen VI accumulates in the extracellular environment. Accumulation can be dramatic and lead to tissue damage and disease. CMG2 also informs the cell of the presence of collagen VI in the extracellular environment. Binding of collagen VI leads to remodelling of the actin cytoskeleton through mechanisms that we are currently investigating.

Gisou van der Goot studied engineering at the Ecole Centrale de Paris, then did a PhD in Molecular Biophysics at the Nuclear Energy Research Center, Saclay, France, followed by a postdoc at the European Molecular Biology Laboratory (EMBL) in Heidelberg. She started her own group in 1994 in the department of Biochemistry, University of Geneva, became Associate professor at the Faculty of Medicine (Univ. Geneva) in 2001 and Full Professor at the EPFL in 2006, where she cofounded the Global Health Institute. In 2014, she was appointed Dean of the School of Life Sciences.

To understand how mammalian cells are compartmentalized, how compartmentalization of specific membranes is achieved and how this is related to function. We are particularly interested in the architecture of the endoplasmic reticulum and how palmitoylation, a uniquely reversible lipidation of proteins, regulates organelle structure and function by targeting key proteins. To understand the physiological and pathological roles of the anthrax toxin receptors, TEM8 and CMG2. These two single spanning membrane proteins that are well known to enable intoxication by anthrax but poorly understood with respect to their role in communicating with the extracellular matrix. They are also palmitoylated and represent a useful model system to study this post-translational modification. To unravel the molecular mechanisms responsible for Hyaline Fibromatosis and GAPO syndromes. These two rare genetic diseases are the result of mutations in the anthrax toxin receptors.

Keywords Palmitoylation, DHHC, TEM8, CMG2, anthrax toxin, endoplasmic reticulum, calnexin.

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S-palmitoylation This is the only reversible lipid modification. As phosphorylation and ubiquitination, it allows the control of protein function, conformation or localization in a switch like manner. To reach mechanistic understanding of palmitoylation, we choose to combine experimental kinetic investigation of protein palmitoylation-depalmitoylation and the consequences thereof on protein stability, localization and function with mathematical modelling. In close collaboration with the laboratory of Vassily Hatzimanikatis (EPFL, Basic Sciences) this approach was successfully applied to the ER chaperone calnexin, providing unprecedented understanding of the dynamics of the modification. This approach was extended to the palmitoyltransferase of calnexin, the DHHC6 enzyme. As the first evidence for palmitoylation cascades, we found that DHHC6 can be modified on 3 sites by an upstream DHHC enzyme. Palmitoylation is controls DHHC6 localization, stability and function. Datadriven mathematical modelling reveals a highly dynamic palmitoylation system that controls the abundance and function of this key ER palmitoyltransferase. As a community tool, we generated the SwissPalm knowledgebase which not only provides relevant information and tools regarding palmitoylation but most importantly allows the analyses of all palmitoyl-proteomes studies reported in the literature.

GHI - Global Health Institute

Team Members Senior Researcher

Laurence Abrami

Post Doctoral Fellows

Mathieu Blanc Oksana Sergeeva Maria Eugenia Zaballa Sarah Friebe Patrick Sandoz Olha Novokhatska PhD Students

Mustafa Demir Numa Piot Technicians

A: Structure of anthrax toxin receptor 2 or CMG2 (taken from The dark sides of capillary morphogenesis gene 2. Deu uet , ausch , uperti-Furga , van der Goot FG. B . 20 2 an ( ) - . doi 0. 0 emboj.2011.442.) B: Schematic illustration of the complexity of palmitoyation networks, in particular in the endoplasmic reticulum

Sylvia Ho Béatrice Kunz Tiffany Thebault, Thomas Jenny Administrative Assistants

Geneviève Rossier

Selected Publications » Blanc, M., David, F., Abrami, L., Migliozzi, D., Armand, F., Bürgi, J. and van der Goot, F.G. (2015) SwissPalm: Protein palmitoylation database. F1000Research 4:261. » Dallavilla, T. #, Abrami, L. #, Sandoz, P.A., Savoglidis, G., Hatzimanikatis, V*. and van der Goot, F.G.* (2016) Model-driven understanding of palmitoylation dynamics: regulated acylation of the endoplasmic reticulum chaperone calnexin. PLoS Computational Biol. 12:e1004774. » Bischofberger, M, Iacovache, I., Boss, D., Naef, F., van der Goot, F.G.* and Molina, N. * (2016) Revealing assembly of a pore-forming complex using single-cell kinetic analysis and modeling. Biophysical J. 110:15741581. » Iacovache, I., De Carlo, S., Cirauqui,, N., Dal Peraro,, M., van der Goot, F.G. and*, Zuber,, B.* (2016) Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore formation process. Nature Com. 7:12062. » Bürgi, J., Xue, B., Uversky, V.N. and van der Goot, F.G. (2016) Intrinsic disorder in transmembrane proteins: Roles in signaling and topology prediction. PLoS One 11:e0158594. » Perrody, E., Abrami, L., Feldman, M., Kunz, B., Urbe, S. and van der Goot, F.G. (2016) Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6. eLife. 5. pii: e19083. » Bürgi, J. Kunz, B., Abrami,, L., Deuquet, J., Piersigilli, A., Scholl-Bürgi, S., Lausch, E., Unger, S., Superti-Furga, A., Bonaldo,, P. and van der Goot, F.G. (2017) CMG2/ANTXR2 is a receptor for collagen VI and controls its extracellular levels. Nature Com. (in press). # Co-first author * Co-senior corresponding author

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Editor: Laurence Mauro Many thanks to Friedrich Beermann, Lucia Baldi, Dietrich Reinhard, Sacha Sidjanski, Harald Hirling and Roland Chabloz at the Repro for their help and support!

12th edition 2015/2016 Produced and edited by the EPFL School of Life Sciences Printed at the EPFL “Atelier de Reprographie”

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