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    Neonates predisposition and the mechanisms leading to GBS invasive infections

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    Principal Investigators

    Julie Guignot and Asmaa Tazi, Claire Poyart

    julie.guignot@inserm.fr ;01 40 51 64 13

    asmaa.tazi@inserm.fr ; 01 40 51 64 55

    claire.poyart@aphp.fr ; 01 58 41 15 60

     

    Objective

     The neonates’ predisposition to CC-17 GBS hypervirulent clone infection and the pathogenesis of GBS meningitis are not well understood. The bacterium can cause both neonatal early-onset disease (< 7 days of life) and late-onset disease (7 to 89 days old). One particular aspect of the perinatal period is the hormonal impregnation to which the neonate is submitted. These hormones, mainly estradiol and progesterone, are known to modulate the immune response and also to modify physiological barriers permeability by modifying expression of uncovered receptors. We will determine whether hormones influence the virulence of CC-17 GBS and its capacity to cross physiological barriers. The molecular mechanisms involved in intestinal and blood-brain barrier crossing by GBS will be addressed.

     

    The group

    Julie GUIGNOT, scientist; Asmaa TAZI, associate professor-hospital practitioner; Claire Poyart, professor-hospital practitioner; Lionel Costa, post-doctoral fellow; Anne-Sophie Bourrel, PhD fellow- hospital practitioner; Agnès Fouet, scientist; Amandine Picart, engineer.

     

    Research interests

    We previously demonstrated that CC-17 GBS expresses, among others, two specific surface proteins, Srr2 and HvgA, that act as adhesins and contribute to virulence and barrier crossing (intestinal or blood-brain barrier) (ref 2 and 5). These adhesins bind fibrinogen and/or plasminogen, two plasmatic components that contribute to the crossing of the BBB by an unknown mechanism.

    • Decipher the role of fibrinogen and plasminogen binding to CC17 GBS pathogenesis
    • Evaluate the role of the phagocytes in CC-17 pathogenesis. Using murine models of intravenous and oral infection by fluorescent bacteria, we will assess the role of professional phagocytes in intestinal and blood-brain barrier crossing.
    • Characterize the impact of perinatal hormonal concentrations on the different steps of CC-17 GBS infectious process, e.g. intestinal translocation, resistance to the host’s immune system and blood-brain barrier crossing. Host-pathogen interactions are studied in cellular and murine models of infection in various hormonal concentrations mimicking those encountered at birth and later.

     

    Figure. CC-17 and CC-23 interaction with intestinal epithelial cells. The epithelium is composed of a monolayer of enterocytes and M cells. The figure shows the specific interaction between CC-17 GBS and M cells involved in intestinal translocation.

     

    Main publications and patents

    1. Tazi A, Plainvert C, Anselem O, Ballon M, Marcou V, Seco A, El Alaoui F, Joubrel C, El Helali N, Falloukh E, Frigo A, Raymond J, Trieu-Cuot P, Branger C, Le Monnier A, Azria E, Ancel PY, Jarreau PH, Mandelbrot L, Goffinet F, Poyart C. Risk Factors for Infant Colonization by Hypervirulent CC17 Group B Streptococcus: Toward the Understanding of Late-onset Disease. Clin Infect Dis. 2019 Apr 4. pii: ciz033. doi: 10.1093/cid/ciz033.

    https://www.ncbi.nlm.nih.gov/pubmed/30946447

    2. Six A, Bellais S, Bouaboud A, Fouet A, Gabriel C, Tazi A, Dramsi S, Trieu-Cuot P, Poyart C. Srr2, a multifaceted adhesin expressed by ST-17 hypervirulent Group B Streptococcus involved in binding to both fibrinogen and plasminogen. Mol Microbiol. 2015 Sep;97(6):1209-22. doi: 10.1111/mmi.13097.

         https://www.ncbi.nlm.nih.gov/pubmed/26094503

    3. Firon A, Tazi A, Da Cunha V, Brinster S, Sauvage E, Dramsi S, Golenbock DT, Glaser P, Poyart C, Trieu-Cuot P. The Abi-domain protein Abx1 interacts with the CovS histidine kinase to control virulence gene expression in group B Streptococcus. PLoS Pathog. 2013 Feb;9(2):e1003179. doi: 10.1371/journal.ppat.1003179.

         https://www.ncbi.nlm.nih.gov/pubmed/23436996

    4. Bellais S, Six A, Fouet A, Longo M, Dmytruk N, Glaser P, Trieu-Cuot P, Poyart C. Capsular Switching in Group B Streptococcus CC17 Hypervirulent Clone: A Future Challenge for Polysaccharide Vaccine Development. J Infect Dis. 2012. 206:1745-1752.

         https://www.ncbi.nlm.nih.gov/pubmed/23002446

    5. Tazi A, Disson O, Bellais S, Bouaboud A, Dmytruk N, Dramsi S, Mistou MY, Khun H, Mechler C, Tardieux I, Trieu-Cuot P, Lecuit M, Poyart C. The surface protein HvgA mediates group B Streptococcus hypervirulence and meningeal tropism in neonates. J Exp Med. 2010 Oct 25;207(11):2313-22.

         https://www.ncbi.nlm.nih.gov/pubmed/20956545

     

    Financial supports

    These programs are supported by

    Grant ANR 2017 StrepB2Brain

    Fondation pour la Recherche Médicale (grant number DEQ20100318279 and DEQ20130326538),

    ANR (grant number ANR-08-GENM-027–001)

    Institut Pasteur

    Institut de Veille Sanitaire

    Research Networks Program in Complexity in Biology: Molecular Aspects of Infectious Diseases (High Council for Scientific and Technological Cooperation between France- Israel)

    ERA PathoGenoMics (grant ANR-08-MIEN-015),

    Fonds d’Études et de Recherche du Corps Médical

    Labex Integrative Biology of Emerging Infectious Diseases (grant number ANR-10-LABX-62-IBEID)

    University Paris Descartes (grant number 641 113 10).

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