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Phage-mediated impact on S. aureus phenotypic and genome plasticity

English title Phage-mediated impact on S. aureus phenotypic and genome plasticity
Applicant François Patrice
Number 153474
Funding scheme Project funding (Div. I-III)
Research institution Laboratoire de Recherche Génomique Service des Maladies Infectieuses Hôpital Cantonal - HUG
Institution of higher education University of Geneva - GE
Main discipline Experimental Microbiology
Start/End 01.06.2014 - 30.09.2017
Approved amount 361'797.00
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Keywords (11)

Staphylococcus aureus; invasiveness; restriction systems; prophages; genome; human infection; host tropism; virulence; page-mediated; livestock; transcriptome

Lay Summary (French)

Lead
Depuis l’apparition des Staphylococcus aureus multi-résistants (SARM) cette bactérie est considérée comme l’archétype du germe nosocomial. Cependant depuis les années 90, les SARM sont également impliqués dans des infections communautaires, chez des personnes jeunes et en bonne santé. Plus récemment la recherche d’un réservoir de S. aureus a ciblé les fermes et les animaux d’élevage. De nombreux animaux ont été identifiés comme porteurs de souches qui leurs sont propres. Dernièrement, cette apparente « barrière d’espèce » a été rompue et l’on note un nombre croissant d’infections humaines sévères impliquant des souches initialement d’origine animale.
Lay summary

Lead

Depuis l’apparition des Staphylococcus aureus multi-résistants (SARM) cette bactérie est considérée comme l’archétype du germe nosocomial. Cependant depuis les années 90, les SARM sont également impliqués dans des infections communautaires, chez des personnes jeunes et en bonne santé. Plus récemment la recherche d’un réservoir de S. aureus a ciblé les fermes et les animaux d’élevage. De nombreux animaux ont été identifiés comme porteurs de souches qui leurs sont propres. Dernièrement, cette apparente « barrière d’espèce » a été rompue et l’on note un nombre croissant d’infections humaines sévères impliquant des souches initialement d’origine animale.

Contenu et objectifs du travail de recherche

L’utilisation des techniques de séquençage à haut débit de différentes populations de SARM montre que leur contenu en bactériophage est spécifique de leur origine. Nous avons récemment identifié un nouveau phage dans des souches animales capables d’infecter l’homme. Des expériences de mobilisation de ce bactériophage suivi de sa réintroduction dans une souche naïve ont montré l’apparition d’un nouveau phénotype. Le prophage semble ainsi être impliqué dans différentes caractéristiques comme i) le tropisme cellulaire, ii) l’expression de facteurs de virulence, iii) la limitation de la plasticité du génome bactérien.

Contexte scientifique du projet de recherche

Ce projet vise à caractériser les gènes et les mécanismes moléculaires impliquant ces bactériophages qui confèrent à la bactérie des propriétés nouvelles et essentielles pour la physiopathologie et la virulence.

 

Mots clés: Staphylococcus aureus, infections humaines, infections animales, bactériophages, système de restriction, génome, transcriptome, invasion, virulence, cellules hôtes

Direct link to Lay Summary Last update: 01.04.2014

Responsible applicant and co-applicants

Employees

Publications

Collaboration

Group / person Country
Types of collaboration
CNRS, IBMC- Strasbourg France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
CHU Trousseau, Tours, France France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dartmouth University, NH, USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SSM-SPB 2019 Individual talk ROLE OF PROPHAGES IN VIRULENCE AND HOST TROPISM OF STAPHYLOCOCCUS AUREUS STRAINS BELONGING TO THE CLONAL COMPLEX 398 29.11.2019 Coppet, Switzerland Laumay Floriane;
Host-Microbe Interaction Retreat Talk given at a conference fbl-Typing of Staphylococcus lugdunensis: A Frontline Tool for Epidemiological Studies, but Not Predictive of Fibrinogen Binding Ability 31.10.2019 Chavanne de Baugis, Switzerland François Patrice; Laumay Floriane;
Phages in Grenoble Talk given at a conference French Phage Network Annual meeting 21.10.2019 Grenoble, France Laumay Floriane;
Advanced Molecular Pathogenesis course Individual talk Use of whole genome sequencing for molecular epidemiology and antimicrobial surveillance 11.10.2018 Geisel School of Medicine, Dartmouth, United States of America François Patrice;


Abstract

Staphylococcus aureus is a versatile human and veterinary pathogenic bacterium recognized as a worldwide health problem. S. aureus is responsible for a wide spectrum of infections, ranging from local skin to severe disseminated diseases. In human, these infections include acute diseases: endocarditis, furonculosis or food-poisoning but also chronic infections such as osteomyelitis, rhinosinusitis or otitis media. Human is not the only host suffering S. aureus infections, livestock such as pigs or poultry are also potential sources of S. aureus and methicillin resistant S. aureus (MRSA), spreading in priority to farmers but also to healthy people without contact with livestock. In livestock, pig and poultry are often colonized whereas in dairy animals mastitis represents the primarycause of milk loss. Note that this disease is often lethal for ewes suffering gangrenous mastitis. In contrast, approximately 20% of the general population carries S. aureus asymptomatically for decades. Methicillin-resistant S. aureus (MRSA) emerged rapidly after the introduction of methicillin and have become a worldwide problem in developed countries since the 80’s. In hospitals globally MRSA is considered the prototype nosocomial pathogen. However, more recently MRSA were also frequently found as causative agents of community acquired infections. Infections due to S. aureus (or MRSA) are particularly diverse in terms of host, infected tissues, as well as severity and difficulty of eradication. This observation suggests that the bacterium would be highly variable in terms of genomic features. However, the totality of clinical manifestations and symptoms are due to only 8-10 different lineages. For example, strains showing sequence type 398 (ST398) were almost exclusively associated with veterinary infections or colonization (pigs and bovines). Then, cases of severe infections were reported in human generally in contact with livestock. In our observations, MSSA from ST398 were absent from the human clinics until 2009. Since this period, ST398 have been increasingly reported as causative agent of severe infections in humans. On an epidemiological point of view, the vast majority of bloodstream infections reported in our area, involved patients without contact with livestock. Genome sequencing of these isolates revealed an absence of a type-IV restriction system, allowing us to expect facilitated genetic manipulations. However, these isolates were totally non-transformable and not typable even using a large diversity of phages. Genomic analysis of collections of ST398 isolates revealed a specific content in bacteriophage for strain populations collected either from animal or from human. In particular, we reported in a recent publication, evidence of a defective ?MR11-like helper prophage associated with the emerging non-livestock associated CC398 subpopulation, conferring new phenotypic characteristics. Indeed, observations obtained from our group suggest that these genetic mobile elements i) frequently contain virulence factors (numerous enterotoxins, potent pore-forming toxins) ii) contribute to genome plasticity iii) modulate interactions with host tissues and cells and iv) dictate host tropism. To date, the direct impact triggered by these phages have never been investigated at the molecular level. The current proposal relies on the utilization of standard and molecular microbiology techniques currently used in our laboratory such as phage mobilization, transduction, transformation, sequencing and annotation, gene expression, targeted mutagenesis, cellular internalization assay. The specific aim of this project is to define in details the molecular mechanisms responsible for the phenotypic effects observed in our recent studies, in particular the increasing cellular invasion capacity and the altered bacterial genome plasticity, with respect to phage content.
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