3 ème Colloque «Montpellier Infectious Diseases» Pôle Rabelais

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1 3 ème Colloque «Montpellier Infectious Diseases» Pôle Rabelais novembre 2014 Genopolys Livre de résumés

2 Session 1 - Infection, transmission and drug design. 1

3 Chromosomal DNA replication and segregation in Leishmania Yvon Sterkers 1, Slavica Stanojcic Etienne Schwob Michel Pagès 1, Patrick Bastien 1, 1 : Laboratoire de Parasitologie-Mycologie, Montpellier (MIVEGEC) - Site web Université Montpellier II - Sciences et techniques, CNRS : UMR5290, Institut de recherche pour le développement [IRD] : UR224, CHRU Montpellier, Université Montpellier I 39, Avenue Charles Flahault, Montpellier - France 2 : Institut de génétique moléculaire de Montpellier (IGMM) - Site web CNRS : UMR5535, Université Montpellier II - Sciences et techniques 1919 Route de Mende MONTPELLIER CEDEX 5 - France * : Auteur correspondant In most biological models, reproduction as identical or similar organisms is based on the extreme accuracy of the mechanisms involved in the even transmission of the genetic material to the two daughter cells. This 'golden rule' does not seem to apply in Leishmania in which asymmetric chromosomal allotments during mitosis are responsible for a unique ploidy organization termed 'mosaic aneuploidy'. To get further insight into this unique feature, we developed an interest in chromosomal replication and segregation which are ill-known in Leishmania. We also studied the 'sister parasite' Trypanosoma brucei, which is diploid and where these key cellular processes are better elucidated. We followed two independent research approaches. First, to determine the physical parameters of the replication process, we analysed DNA replication dynamics in these parasites using DNA molecular combing; this allowed showing particularly large inter-origin distances and high speeds of DNA replication forks. Second, we studied the chromosomal dynamics during mitosis. Using fluorescent in situ hybridization combined with immunofluorescence in T. brucei procyclic forms, we determined the spatiotemporal dynamics of (i) the centromeres of chromosome II and III, and (ii) TbMlp2, the ortholog of a nucleoporin, during the course of the cell cycle. In interphase, the centromeres and TbMlp2 were located at the periphery of the nucleolus. TbMlp2 was then seen progressively migrating from the periphery of the nucleolus to the spindle poles. The position of the centromeres remained unchanged until TbMlp2 had completed migration to the spindle pole; then the centromeres themselves started migrating to the poles. In addition, RNAi knockdown of TbMlp2 lead to aneuploidy. Altogether, these data suggest that, unexpectedly, TbMlp2 may play a key role, as a molecular chaperone and/or transport protein, in the dynamics of chromosomal segregation. In total, both approaches again revealed original features in these divergent eukaryotes as compared to classical models. 2

4 Wolbachia interactions with its filarial nematode host: transmission mechanisms and roles of the symbiont. Frederic Landmann 1 : Centre de Recherche de Biochimie Macromoléculaire (CRBM) - Site web CNRS : UMR5237 CNRS-UMR , Route de Mende Montpellier Cedex 5 FRANCE - France Wolbachia are gram-negative, obligate, intracellular bacteria carried by millions of arthropods worldwide. Wolbachia are also symbiotic with filarial nematodes, but exclusively with members of the parasitic Onchocercidae family. Wolbachia are transmitted vertically through the female germline, similar to mitochondria. In nematodes, the Wolbachia-host symbiosis has evolved toward mutualism and bacteria removal interferes with worm development and eventually leads to nematode death. Filarial nematodes are causative agents of devastating diseases such as elephantiasis and river blindness. These diseases affect ~120 million people in tropical areas. There is currently no drug treatment against adult filarial nematodes. Because Wolbachia is essential to adult worm survival and fertility, Wolbachia is a promising drug target. Using Brugia malayi as a filarial model, a causative agent of elephantiasis, we are focusing on two fundamental aspects of this symbiosis : - the mechanisms of Wolbachia transmission, from the fertilized egg to the adult tissues. - the role and contribution of symbionts to the filarial host. Using cell biology techniques we designed for studying these parasitic worms, we show that Wolbachia asymmetrically segregate during embryogenesis to reach only the hypodermis of the worm, and an ovarian tropism allows the symbionts in the hypodermis to colonize the adult female germline. We will present the defects induced during oogenesis and embryogenesis in the absence of Wolbachia. 3

5 Identification of inhibitors of PfCCT, a key enzyme of Plasmodium falciparum membrane biosynthesis Alicia Contet Ewelina Guca 1, Emilie Pihan Marina Lavigne François Hoh Jean-François Guichou Henri Vial Dominique Douguet Rachel Cerdan 1 : Dynamique des interactions membranaires normales et pathologiques (DIMNP) - Site web CNRS : UMR5235, Université Montpellier I, Université Montpellier II - Sciences et techniques BT 24 CC 107 Place Eugène Bataillon MONTPELLIER CEDEX 5 - France 2 : Centre de Biochimie Structurale (CBS) - Site web Inserm : U1054, Université Montpellier II - Sciences et techniques, CNRS : UMR5048, Université Montpellier I 29 rue de Navacelles MONTPELLIER Cedex - France - France 3 : Institut de pharmacologie moléculaire et cellulaire (IPMC) - Site web CNRS : UMR7275, Université Nice Sophia Antipolis (UNS) CNRS-IPMC 660 Route des lucioles VALBONNE - France During its life cycle in the human erythrocyte, Plasmodium falciparum, the parasite responsible of malaria, relies on phospholipids to build the membranes necessary for daughter cell development. The parasite membranes are composed of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) which together represent approx. 80% of the total membrane lipids. In P. falciparum, PC and PE are synthesized by the parasite's machinery through the de novo CDP-choline and CDP-ethanolamine (Kennedy) pathways using choline or ethanolamine as precursors. Our studies focus on the two cytidylyltransferases : PfCCT and PfECT. These enzymes catalyze the rate-limiting step of their respective pathway and both contain two cytidylyltransferase domains. Here we focus on the biochemical characterization and the inhibition of PfCCT. Interestingly, both catalytic domains of PfCCT are active while site-directed mutagenesis revealed that only one domain of PfECT is active, suggesting substantial evolutionary differences within this protein family3. Recently, we obtained the 3D crystal structure at 2.4 Å resolution of the C-terminal catalytic domain of PfCCT in complex with its reaction product CDP-choline. By virtual screenings of commercial compounds using docking tools, we identified molecules that competitively inhibit PfCCT activity. We are also developing a second approach for the identification of PfCCT inhibitors by fragment-based drug design. Primary screening of fragment library (230 molecules) has been performed by fluorescence-based thermal shift assay followed by Nuclear Magnetic Resonance Saturation Transfer Difference (NMR STD) as secondary screen to eliminate false positive ligands. Cocrystallization of the protein-fragments complexes will then be used for the optimization process, allowing subsequent rational design of inhibitors of this key enzyme of P. falciparum membrane biosynthesis. 4

6 Rationnal Design of small-molecules inhibitors of human Cyclophilins and HCV replication by Structure Based Drug Design. Jean-François Guichou 1, Jean-Michel Pawlotsky 1 : Centre de Biochimie Structurale Inserm : U554, CNRS : UMR5048, Université Montpellier I, Université Montpellier II - Sciences et Techniques du Languedoc 2 : Centre de Biochimie Structurale (CBS) Inserm : UMR : hopital henri mondor Hôpital Henri Mondor The hepatitis C virus (HCV) is the leading cause of chronic hepatitis, of liver cirrhosis and hepatocellular carcinoma. Roughly 170 millions individuals are infected in the whole world and the infection by HCV causes approximately deaths per year. The study of the complex of replication made it possible to highlight the crucial role of cellular partners, in particular the cyclophilins1, in the driving process with the synthesis of new viral genomes and inhibition of these enzymes lead to new anti-viral agents. The Cyclophilins are enzymes that have been observed abundantly and ubiquitously in a wide range of tissue types and organisms. They are characterized by the ability to catalyse the cis-trans isomerisation of peptidylprolyl bonds2 (PPIases) which was identified as the rate-limiting step in protein folding. To design news Cyps inhibitors with low molecular mass, we applied a fragmentbased screening approach on Cyclophilin D (CypD). We used X-ray crystallography and NMR that are well adapted to identify weak affinity fragments (mm). We solved 14 crystallographic structures of CypD in complex with fragments (2,00-0,97Å). Based on the fragments binding modes, we designed and optimized a new Cyps inhibitors family (proline mimetic). Our lead compound have an IC50 of 10 nm on CypD and CypA in vitro and an EC50 of 15 nm for the HCV replication in cellulo. The presentation will show the used of X- ray crystallography for the discovery of news human Cyps and HCV inhibitors. [1] Rice M.C., Top. Antivir. Med., 2011, 19(3): [2] Galat, A., Eur J Biochem, 1993, 216 :

7 Investigation of capsid determinants involved in nepovirus transmission: a hybrid structural approach Patrick Bron 1 : Centre de Biochimie Structurale (CBS) - Site web Inserm : UMR1054, CNRS : UMR5048, Université Montpellier II - Sciences et Techniques du Languedoc, Université Montpellier I 29 rue de Navacelles MONTPELLIER Cedex - France - France Arabis mosaic virus (ArMV) and Grapevine fanleaf virus (GFLV) are two picorna-like viruses from the genus Nepovirus, consisting in a bipartite RNA genome encapsidated into a 30 nm icosahedral viral particle formed by 60 copies of a single capsid protein (CP). They are responsible for a severe degeneration of grapevines that occurs in most vineyards worldwide. Although sharing a high level of sequence identity between their CP, ArMV is transmitted exclusively by the ectoparasitic nematode Xiphinema diversicaudatum whereas GFLV is specifically transmitted by the nematode X. index. The structural determinants involved in the transmission specificity of both viruses map solely to their respective CP. We present here a structural study that allowed us to identify a charged pocket involved in specificity of transmission of Nepovirus by hybrid approach combining X-ray crystallography, cryoelectron microscopy, single particle analysis and molecular dynamics methods. 6

8 The Two Human CXCR4 Isoforms Display Different HIV Receptor Activities: Consequences for the Emergence of X4 Strains Charline Duquenne Christina Psomas Sandrine Gimenez Adeline Guigues Marie-Josée Carles Claudine Barbuat Jean-Philippe Lavigne Albert Sotto Jacques Reynes Paul Guglielmi Clément Mettling Vincent François Pierre Corbeau 1 : IGH CNRS : UPR : CHU Montpellier CHU Montpellier 3 : CHU Nîmes CHU Nîmes 4 : UM2 UM2 5 : IGH CNRS : UPR1142, CNRS CXCR4 is a chemokine receptor that plays key roles with its specific ligand, CXCL12, in stem cell homing and immune trafficking. It is also used as a coreceptor by some HIV-1 strains (X4 strains), whereas other strains (R5 strains) use an alternative coreceptor, CCR5. X4 strains mainly emerge at late stages of the infection and are linked to disease progression. Two isoforms of this coreceptor have been described in humans, CXCR4-A and CXCR4-B, corresponding to an unspliced and a spliced mrna, respectively. Here, we show that CXCR4-B, but not CXCR4-A, mediates an efficient HIV-1 X4 entry and productive infection. Yet, the chemotactic activity of CXCL12 on both isoforms was similar. Furthermore, HIV-R5 infection favored CXCR4-B expression over that of CXCR4-A. In vitro infection with an R5 strain increased CXCR4-B : CXCR4-A mrna ratio in peripheral blood mononuclear cells (PBMC), and this ratio correlated with HIV RNA plasma level in R5-infected individuals. In addition, the presence of the CXCR4-B isoform favored R5 to X4 switch more efficiently than CXCR4-A in vitro. Hence, the predominance of CXCR4-B over CXCR4-A expression in PBMC was linked to the capability of circulating HIV-1 strains to use CXCR4, as determined by genotyping. These data suggest that R5 to X4 switch could be favored by R5 infectioninduced overexpression of CXCR4-B. Finally, we achieved a specific sirna-mediated knockdown of CXCR4-B. This represents a proof of concept for a possible gene therapeutic approach aimed at blocking the HIV coreceptor activity of CXCR4 without knocking down its chemotactic activity. 7

9 Session 2 - Infection, immunity and regulation 8

10 Identification and characterization of Mabs_4780, a new determinant required for intracellular survival and pathogenicity of Mycobacterium abscessus Iman Halloum 1, Séverine Carrère-Kremer Vipul Singh Audrey Bernut Georges Lutfalla Laurent Kremer 1 : Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques (DIMNP) - Site web CNRS : UMR5235 CNRS-Université de Montpellier II Montpellier cedex 5 - France 2 : Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques (DIMNP) CNRS : UMR : Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques CNRS : UMR : Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques (DIMNP) - Site web CNRS : UMR5235 Université Montpellier 2 Bât 24 2 étage Place Eugène Bataillon Montpellier cedex 5 France - France * : Auteur correspondant Mycobacterium abscessus (Mabs) is an emerging rapid-growing mycobacteria causing severe lung infections, particularly in cystic fibrosis patients. The smooth morphotype displays surface expression of glycopeptidolipids (GPLs) whereas the rough morphotype is characterized by the loss of surface GPL. Rough variants are involved in more severe clinical forms although the underlying physiopathological mechanisms remain obscure. We have recently developed a zebrafish embryo model to decipher the pathogenesis of Mabs and the chronology of the infection process. Herein, we evaluated the contribution of MABS_4780 in rough Mabs virulence. A mutant was constructed in which MABS_4780 was disrupted by a hygromycin cassette. This strain exhibited a higher susceptibility to thiacetazone, a second-line antitubercular drug, compared to the parental strain and higher sensitivity to detergents, presumably due to alterations of cell wall composition/structure. Consistent with hypothesis, solving the three-dimensional structure of the M. smegmatis orthologue revealed a MaoC-like structure of known dehydratases, potentially involved in cell wall lipid biosynthesis. Since Amoeba may represent the environmental reservoir of Mabs, we also assessed the intracellular fate of the mutant in Acanthamoeba Castellanii. The mutant failed to replicate intracellularly but this growth defect was not due to a general metabolic abnormality since it grew similarly to parental strain in vitro. In addition, unlike the R variant, the mutant strain was extremely attenuated in infected zebrafish embryos and was unable to produce abscesses within the central nervous system and to kill the embryos. Our findings demonstrate the unanticipated role of MABS_4780 in physiopathology of Mabs infection, emphasizing its potential as an attractive drug target. 9

11 Phosphorylation of proteins and bacterial pathogenicity Virginie Molle 1 : UMR5235 (DIMNP) - Site web CNRS, UM2 DIMNP-University Montpellier 2 Place Eugene Bataillon Montpellier - France The importance of reversible protein phosphorylation to cellular regulation cannot be overstated. In eukaryotic cells, protein kinase/phosphatase signaling pathways regulate a staggering number of cellular processes including cell proliferation, cell death, metabolism, behavior and neurological function, development and pathogen resistance. While protein phosphorylation as a mode of eukaryotic cell regulation is familiar, many are less familiar with protein kinase/phosphatase signaling networks that function in prokaryotes. Of particular interest, the persistence of bacterial infections in humans and the emergence of antibiotic-resistant strains emphasize the need for novel therapeutic approaches. In order to sustain treatment of bacterial infections in humans, identification of novel drug targets is pivotal. Thus, a greater understanding of molecular mechanisms underlying bacterial disease pathogenesis is essential for the identification and further development of novel drug targets. The discovery of eukaryotic-like signaling systems, such as STPKs (Serine/Threonine Protein Kinases) and phosphatases in bacterial pathogens has sparked an interest in understanding their function. This is partly due to the fact that eukaryotic protein kinases are currently the largest group of drug targets, second only to G-protein-coupled receptors. Therefore, studies on the importance of prokaryotic STPKs in human pathogens have gained interest owing to the prospect that these signaling components may be useful in future anti-infective therapies and that a complete understanding of their role is a prerequisite for future evaluation of these enzymes as antimicrobial targets. The increased understanding of their widespread occurrence and the importance of the processes they control emphasize the significance of these eukaryotic-like signaling systems in prokaryotes and especially in pathogens. Although STPKs and phosphatases regulate important functions in bacterial pathogens, our understanding of the signal transduction mechanism is still in its infancy. The contribution of these signaling enzymes to bacterial growth and pathogenesis is multifaceted as can be expected for any signaling system. In our group, we are exploring the mechanism for how these signaling enzymes mediate diverse functions in a coordinated fashion as it remains to be completely understood. 10

12 Host immune response and macrophage behaviour during Burkholderia cepacia complex infection in zebrafish embryos Jennifer Mesureur Annemarie Meijer Annette Vergunst 1 : Virulence Bactérienne et Maladies Infectieuses Inserm : U1047, Université Montpellier I UFR Médecine, CS , chemin du carreau de Lanes NIMES Cedex 02 - France 2 : Gorlaeus Laboratory Institute of Biology, Leiden University Gorlaeus Laboratory, Cell Observatory, Einsteinweg 55, 2333 CC Leiden, The Netherlands - Pays-Bas 3 : Virulence Bactérienne et Maladies Infectieuses Inserm : U1047, Université Montpellier I UFR Médecine, CS , chemin du carreau de Lanes NIMES Cedex 02 France - France Chronic respiratory infection in cystic fibrosis patients is characterized by a high level of proinflammatory cytokines, leukocyte infiltration, and inflammation in the lungs due to colonization by pathogenic bacteria. Chronic infections caused by bacteria belonging to the Burkholderia cepacia complex (Bcc) can be symptom free, but often cause pulmonary exacerbation with progressive worsening of lung function, sometimes resulting in acute fatal necrotizing pneumonia and sepsis. The reasons for these unpredictable, sudden transitions are not understood. Using zebrafish embryos, which have an innate immune system very similar to that of humans, we previously found that B. cenocepacia K56-2, belonging to the epidemic ET12 lineage, is highly virulent for zebrafish embryos; it causes a rapidly fatal (2 days) systemic inflammatory infection. In contrast, embryos can control infection with strains such as B. stabilis LMG14294, which cause a persistent infection. Intravenously injected bacteria are rapidly phagocytosed by macrophages, and we found that an intracellular stage is important for fatal infection. In an attempt to better understand the molecular basis for B. cenocepacia K56-2 or B. stabilis LMG14294 infection outcomes, we performed a global host transcriptome analysis during different stages of both infection types. RNA-seq analysis revealed interesting infection responsive host gene expression patterns. Whereas many host genes were differentially regulated during early (3 hours) as well as later (24 hours) stages of infection caused by B. cenocepacia K56-2, only few genes showed changes in expression level upon persistent infection with B. stabilis LMG In particular, the innate immune response with Toll-like receptor (TLR), NOD-like receptor and apoptosis pathways were strongly activated during acute infection. The silent intracellular persistence of B. stabilis coincided with increased expression of genes encoding complement proteins. We will discuss how we are using the zebrafish model to further study the role of the TLR pathway, including the central adaptor protein MyD88 and intracellular stages in the induction of the highly excessive innate inflammatory response. 11

13 Role of the transcriptional regulator RegA in establishment of Brucella suis persistence in an original in vitro model Elias Elias Abdou1, Ignacio Martinez-Abadia1, Véronique Pantesco2, Sascha Al Dahouk3, Stephan Köhler1, Veronique Jubier-Maurin1 1, 2, 1 : 1Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), UMR5236 CNRS; Université Montpellier 1 ; Université Montpellier 2 CNRS : UMR : 2Institute for Research and Biotherapy, CHU Saint-Eloi, Inserm U1040, Montpellier Centre de Recherche Inserm 3 : 3Federal Institute for Risk Assessment, Berlin, Germany (BFR) Berlin - Allemagne Oxygen deficiency is one of the environmental conditions encountered by Brucella during intramacrophagic replication and chronic infection of the host. At chronic stage of brucellosis, these bacteria can reside in immune structures where anoxic conditions predominate. Our previous studies demonstrated the high metabolic flexibility of Brucella suis with respect to oxygen deprivation. We evidenced the central role of the two-component system RegB/RegA in the coordinated control of oxidative respiration and denitrification respiratory systems, which are crucial for virulence and/or persistence in vivo. More importantly, RegA was found to be essential for B. suis persistence in mice. Recently, we developed an original in vitro model, characterized by progressive oxygen deprivation, which allowed to show that RegA is essential for optimal long-lasting in vitro persistence. To identify RegA-dependent genes and proteins in this model, global transcriptome analysis and whole proteome quantifications were performed by comparison of the wild-type B. suis to a rega mutant strain. These analyses were performed at the time point where anaerobic conditions become established, corresponding to the cessation of wild-type strain multiplication. Genetic validation by quantitative PCR (RT-qPCR) indicated that RegA potentially regulates 12% of the B. suis genes. The down-regulation of genes or proteins involved in cell envelope biogenesis and in cellular division suggests that RegA could be involved in establishment of a non-replicative state. In addition, RegA-dependent repression of an important number of genes involved in energy production may be indicative of a participation of RegA in the slowing-down of central metabolim as it enters into the persistence phase. This was substantiated by the finding that two-thirds of the differentially produced proteins belonging to this functional class were also found repressed, among which isocitrate lyase, the first enzyme of the glyoxylate shunt. Several genes of the virb operon were also found repressed by RegA as was its regulator VjbR. In conclusion, RegA was found to regulate genes that encode proteins of all functional groups. This makes the two-component system RegB/RegA a main regulatory system required for adaptation of B. suis to oxygen depletion, which can contribute to the constraint of bacterial growth, characteristic of chronic infection. 12

14 Characterization of RbpA a master regulator of gene expression from Mycobacterium tuberculosis Ayyappasamy Sudalaiyadum Perumal Rishi Kishore Vishwakarma Zakia Morichaud Francoise Roquet-Baneres Konstantin Brodolin 1, 1 : Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS) - Site web Centre d études d agents Pathogènes et Biotechnologies pour la Santé CPBS - UMR 5236 / CNRS - UM1 / UM route de Mende MONTPELLIER Cedex 5 - France * : Auteur correspondant RbpA, a RNA polymerase binding transcriptional activator protein from Mycobacterium tuberculosis (Mtb), regulates transcription without binding to the double stranded DNA. RbpA is involved in unwinding of the promoter DNA in transcription complexes containing either the housekeeping sigma factor sigma A (σa) or the stress-response sigma factor sigma B (σb). RbpA, predominantly found in actinomycetes, increases the tolerance levels to antibiotics including Rifampicin, most commonly used antibiotic against tuberculosis (the second infection causing highest number of deaths). By using the in-vitro transcription system (IVTS) and electrophoretic mobility shift assays (EMSA), we showed that the action of RbpA is sequence specific, as transcription from the housekeeping sigap promoter of Mtb requires RbpA for activation, but another housekeeping promoter of B. subtilis, sinp3 doesn't require RbpA for the activation. Furthermore, series of mutations of the nucleotides upstream of the sigap promoter suppressed the promoter dependency on RbpA. Thus, the fact that RbpA is involved in RNA polymerase - σa and σb mediated transcriptional activation and increased tolerance to rifampicin, corroborates its role in global regulation of the antibiotic-induced stress in Mycobacterium. Hence, a new approach for Mtb, known as Run-off microarray (ROMA), has been elaborated using in-vitro transcription on genomic DNA, for studying the genome-wide regulation of the gene expression by RbpA. 13

15 Life Technologies - Technologies CRISPR/TALS (genome editing), nouvelles stratégies de clonage et synthèse de gène Chady Jaber 1, Andy Tempez 1 : Life Technologies Thermo Fisher Scientific * : Auteur correspondant CRISPRs and TALs are innovative technologies for genome editing. They provide the ability to target, edit and regulate expression at defined sequences within the genome and enable researchers to more accurately study and engineer gene function and develop better cell models. Life Technologies offers a unique flexibility and accessibility to these technologies through its customized solutions. Furthermore, Life Technologie propose powerful and versatile cloning and expression vectors, GeneArt gene synthesis and assembly tools, and molecular biology essentials for that critical first step in your experiment. Experience the full GeneArt portfolio for your molecular biology projects and outperform conventional techniques in many aspects from time and economization to expression optimization, stability and quality. 14

16 Session 3 - Epidemiology, clinical trials and emerging pathogens 15

17 Dynamic of the Hand, Foot and Mouth Disease in Hai Phong city, Vietnam Patrice Ravel 1, Nghia Ngu Duy 2, Laurent Gavotte 3, Emmanuel Cornillot 1,4,*, Roger Frutos 1,5,* 1 : Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), UMR5236 CNRS, UM1, UM2, Montpellier, France 2 : NIHE - National Institute of Hygiene and Epidemiology, Ho Chi Minh, Vietnam. 3 : Institut des Sciences de l'evolution - Montpellier (ISEM) UMR5554 CNRS, IRD, UM2 4 : Institut de Biologie Computationnelle, Montpellier, France 5 : CIRAD - Centre de coopération internationale en recherche agronomique pour le développement (TA-A17/G), Baillarguet, France * : Auteur correspondant Contact : Hand, foot and mouth disease (HFMD) is an acute febrile illness in children with a papulovesicular skin rash at the palms or soles of the feet, or both. HFMD is caused by members of Human Enterovirus A family of viruses which include Coxsackievirus A (CVA) and Human Enterovirus 71 (EV71). A large scale HFMD epidemic was reported for the first time between 2011 and 2012 in Northern Vietnam. We focus our attention on the large cityharbour of Hai Phong. Two main aspects were studied. The first consisted of determining and understanding the high level of diversity of the clinical signs using the three most solid clinical quantitative parameters; i.e., age, severity score and delay of time of onset to admission from the clinical data set of the observed cases. A hierarchical classification approach was used to cluster the patients into groups of common symptoms and analyze their distribution over the span of the epidemic. The second consisted in analyzing the spread of HFMD according to time and space. The commune is the smallest subdivision of Hai Phong City. Using the commune for geographical localization and the time distribution of the detected cases, recording was done in Geographic Information System (QGIS). The data were used to create a graph that modelised the outbreak of HFMD. Numerical analyses were investigated to determine some group of communes that presented similarities concerning the spatial dynamic of HFMD.* 16

18 HIV patients under suppressive antiretroviral therapy present with various patterns of immune activation: the ACTIVIH study Christina Psomas Mehwish Younas Renaud Cezar Edouard Tuaillon Claudine Barbuat Erika Nogue Christelle Reynes Pierre Portales Pierre Corbeau Jacques Reynes 1 : CHU Montpellier CHU Montpellier 2 : CHU Nîmes CHU Nîmes 3 : EA 2415 UM1 4 : IGH CNRS : UPR1142 Background: HIV infection induces an immune activation fuelled by several causes that may occur in various combinations. These causes are reduced under highly active antiretroviral therapy (HAART), but usually not abolished. In the ACTIVIH study, we analyzed whether immune activation is qualitatively the same for all efficiently treated patients or whether different patterns of immune activation may be identified. Methods: To this aim, we measured in 120 HIV-positive adults, aviremic under HAART for at least 2 years, 55 cell surface and soluble markers of inflammation, and CD4+ T cell, CD8+ T cell, B cell, NK cell, monocyte, and neutrophil activation. We clustered the dataset using two independent hierarchical clustering analyses: one for variables using the 1-r² (where r is the linear correlation coefficient) as a distance between variables, and one for observations using usual Euclidean distance measured on scaled variables for observations. Results: The level of many markers of immune activation were increased, but not altogether in a given patient. We identified various subpopulations of patients according to their pattern of immune activation (Figure). Using ANOVA results corrected by False Discovery Rate for multiple testing, more than 90% of variables were on average significantly different for at least one subpopulation of patients with regards to the other ones (p-value < 0.05). Conclusions: These different patterns of immune activation may be the result of different causes, and may result in different pathogenic consequences. A better understanding of the links between causes, patterns, and consequences of immune activation in virologic responders might pave the way to the identification of markers predictive of specific comorbidities, and to an etiologic and/or symptomatic immunosuppressive therapeutic approach tailored to each subpopulation of patients. 17

19 Gender differences in adherence and response to antiretroviral treatment in the Stratall trial in rural disctrict hospitals in Cameroon Charlotte Boullé Charles Kouanfack Gabrièle Laborde Balen Avelin Agkokeng Maria Patrizia Carrieri Serge Kazé Marlise Dontsop Jean-Marc Mben Sinata Koulla-Shiro Gilles Peytavin Bruno Spire Eric Delaporte Christian Laurent 1 : UMI VIH/SIDA et maladies associées (TransVIHMI) - Site web Université Cheikh Anta Diop (Dakar, Sénégal), Universtié Yaoundé 1 (Cameroun), Université Montpellier I, Institut de recherche pour le développement [IRD] : UR233 Centre IRD France Sud 911, avenue Agropolis BP F Montpellier cedex 5 - France 2 : INSERM U912 SESSTIM, Université Aix Marseille Université de la Méditerranée - Aix-Marseille II 3 : Hopital Central de Yaoundé P- P pital Bichat-Claude Bernard, Laboratoire de Pharmaco-Toxicologie, Paris Assistance publique - Hôpitaux de Paris (AP-HP), Institut National de la Santé et de la Recherche Médicale - INSERM Background: Evidence of gender differences in antiretroviral treatment (ART) outcomes in sub-saharan Africa is conflicting. Our objective was to assess gender differences in 1) adherence to ART and 2) virologic failure, immune reconstitution, mortality, and disease progression adjusting for adherence. Methods: Cohort study among 459 ART-na ve patients followed-up 24 months after initiation in in nine rural district hospitals. Adherence to ART was assessed using 1) a validated tool based on multiple patient self-reports and 2) antiretroviral plasma concentrations. The associations between gender and the outcomes were assessed using multivariate mixed models or accelerated time failure models. Results: One hundred thirty-five patients (29.4 %) were men. At baseline, men were older, had higher BMI and hemoglobin level, and received more frequently efavirenz than women. Gender was not associated with self-reported adherence (P=0.872, and for moderate adherence, low adherence and treatment interruption, respectively) or with antiretroviral plasma concentrations (P=0.549 for nevirapine/efavirenz). By contrast, male gender was associated with virologic failure (odds ratio 2.18, 95 %CI , P=0.003), lower immunologic reconstitution (coefficient at month 24, 95 %CI ;-16.6, P=0.006), and faster progression to death (time ratio [TR] 0.30, 95 %CI , P=0.014) and/or to WHO stage 4 event (TR 0.27, 95 %CI , P=0.017). Conclusions: Our study provides important evidence that African men are more vulnerable to ART failure than women and that the male vulnerability extends beyond adherence issues. Additional studies are needed to determine the causes for this vulnerability in order to optimize HIV care. However, personalized adherence support remains crucial. 18

20 Chikungunya virus-host interplay at the keratinocyte level Laurence 1 : Centre d études d agents Pathogènes et Biotechnologies pour la Santé (CPBS) CNRS UMR 5236, CNRS, CPBS, 1919 route de Mende F Montpellier, France. Université Montpellier 1, université montpellier 2, CNRS : UMR5236 Transmission of chikungunya virus (CHIKV) to humans is initiated by puncture of the skin by a blood-feeding Aedes mosquito. Despite the growing knowledge accumulated on CHIKV, the interplay between skin cells and CHIKV following inoculation still remains unclear. In this study we questioned the behavior of human keratinocytes, the predominant cell population in the skin, following viral challenge. We report that CHIKV rapidly elicits an innate immune in these cells leading to the enhanced transcription of type I/II and type III interferon genes. Concomitantly, we show that despite viral particles internalization into Rab5-positive endosomes and efficient fusion of virus and cell membranes, keratinocytes poorly replicate CHIKV as attested by absence of nonstructural proteins and genomic RNA synthesis. Accordingly, human keratinocytes behave as an antiviral defense against CHIKV infection rather than as a primary targets for initial replication. This picture significantly differs from that reported for Dengue and West Nile mosquito-borne viruses. 19

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