Skip to Main content Skip to Navigation
Theses

Epidémie clonale d'infections invasives à méningocoque de groupe B en Normandie : caractérisation d'un facteur de virulence - HmbR, système d'acquisition du fer via l'hémoglobine - et analyse de la protection conférée par un vaccin à base de vésicules de membrane externe

Abstract : This thesis work includes two studies which both contribute to analyze a posteriori an outbreak of invasive meningococcal diseases (IMD) that had occurred in Normandy from 2003 to 2012 due to the expansion of a single hypervirulent clone (B:14:P1.7,16/ST-32 ). The first work (published in Virulence: Sevestre et al 2018 ;9 :923-929) focused on the virulence determinants of “B14” by comparing 6 isolates, either from IMD or from asymptomatic carriage (these latter expressing or not the capsule). Apparently identical on the basis of classical typing methods (immunotyping and MLST genotyping), these 3 groups of isolates were markedly different by whole genome analysis and on gene by gene comparison (more than 600 genes presenting a variable genetic profile). This analysis leaded to identify the crucial implication of iron acquisition in virulence and in particular the place of the HmbR system, an hemoglobin receptor. In a murine model (transgenic mice made susceptible to infection), these 3 groups also appeared separated, with a distinct infectivity hierarchy (bacterial counts, levels of cytokines). The restoration of the HmbR system in the capsulated carriage isolates (switch from Off phase to On phase) also restored their invasiveness in vitro and in vivo. Even if iron is already known to be a determining factor in the virulence of many bacterial species, our results clearly indicate the importance of the hmbR phase variation among clonal epidemic isolates, allowing adaptation to carriage, sine qua non condition for people to people transmission. The second work (published in Vaccine: Sevestre et al 2017 ;35 :4029-4033) concerned the durability and the cross-protection of the MenBvac®, an OMV vaccine (Outer Membrane Vesicles), used in the past to control the outbreak. This work has been done thanks to 2 cohorts of children vaccinated with 4 doses and sampled either 1 year or 4 years after the last dose. The efficacy (serum bactericidal activity against the epidemic strain) was short lasting, with 48% of children protected after 1 year and 31% after 4 years, a result in accordance with OMV literature. A bactericidal effect was observed far beyond “B14”, by cross-immunity with strains harboring homologies, even partials of the porin PorA (main antigenic determinant in OMV vaccine), indicating a coverage for 15% of virulent isolates B circulating in France, an original result as until then not so far investigated.
Complete list of metadatas

Cited literature [473 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-01929899
Contributor : Abes Star :  Contact
Submitted on : Wednesday, November 21, 2018 - 2:43:06 PM
Last modification on : Friday, April 24, 2020 - 2:22:02 PM
Long-term archiving on: : Friday, February 22, 2019 - 2:14:47 PM

File

juliensevestre.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-01929899, version 1

Citation

Julien Sevestre. Epidémie clonale d'infections invasives à méningocoque de groupe B en Normandie : caractérisation d'un facteur de virulence - HmbR, système d'acquisition du fer via l'hémoglobine - et analyse de la protection conférée par un vaccin à base de vésicules de membrane externe. Maladies infectieuses. Normandie Université, 2018. Français. ⟨NNT : 2018NORMR047⟩. ⟨tel-01929899⟩

Share

Metrics

Record views

217

Files downloads

701