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How Staphylococcus aureus CC398-borne lysogenic bacteriophages im-pact bacterial virulence and genome plasticity

English title How Staphylococcus aureus CC398-borne lysogenic bacteriophages im-pact bacterial virulence and genome plasticity
Applicant François Patrice
Number 197734
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 Medical Microbiology
Start/End 01.12.2020 - 30.11.2023
Approved amount 240'000.00
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Keywords (11)

Evolution; Bacterial virulence; Live-stock; Clonal complex 398; Virulence factors; Staphylococcus aureus; Prophage; Adhesin genes ; Regulation; Human infection; Virulence

Lay Summary (French)

Lead
Comment les prophages de Staphylococcus aureus de la lignée CC398 influencent-ils la virulence bactérienne
Lay summary

          Avant-propos

Staphylococcus aureus colonise de façon asymptomatique 20 à 30% des individus mais est aussi responsable de nombreuses infections de sévérité diverses ; parfois bénignes mais aussi potentiellement mortelles. S. aureus possède une formidable capacité d’adaptation, de production de toxines ou d’acquisition de gènes de résistance. Ces caractéristiques font de S. aureus une bactérie classée par l'OMS parmi les agents pathogènes hautement prioritaires.

     Contenu et objectifs

La lignée CC398 de S. aureus a initialement été décrite comme colonisant les animaux d’élevage mais est devenue en une décennie, un génotype prévalent en médecine humaine. Nos hypothèses veulent que l'acquisition de prophages est responsable de l’évolution vers un phénotype virulent et que le contenu prophagique dicte la virulence des souches. Dans ce projet, nous souhaitons identifier les produits phagiques déterminant la virulence bactérienne. Nous allons établir si ces prophages apportent de nouveaux facteurs de virulence ou s’ils régulent la virulence bactérienne intrinsèque.

 

          Contexte scientifique et social

Le projet relève de la recherche fondamentale mais aura des implications cliniques. Nos travaux sont à l’origine d’une modification des recommandations pour l’utilisation des prophages en thérapeutique humaine. La compréhension des processus de fonctionnement des prophages nous permettra également d’améliorer leur utilisation en thérapie humaine.

Direct link to Lay Summary Last update: 02.10.2020

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Abstract

Staphylococcus aureus is a ubiquitous human and veterinary pathogen recognized as a worldwide health problem. It colonizes the skin of 20-30% of healthy individual but is also responsible for a wide spectrum of infections, ranging from local benign skin to severe disseminated diseases such as endocarditis or osteomyelitis. In the hospital environment, the bacterium shows remarkable capacity to adapt its metabolism to environmental changes including antimicrobial, biocides or host defenses pressure. The severity of clinical presentations as well as emergence of resistant organisms are frequently due to acquisition of mobile genetic elements which occurs quite frequently even if the bacterium harbors active systems that contribute to limit genome plasticity. Despite highly different clinical manifestations, the number of staphylococcal lineages involved in the human and veterinary clinics is limited to approximately 10 lineages. Punctually, highly successful lineages emerged in the clinic showing specific resistance determinants or metabolic advantages. In the epidemiological context, strains belonging to clonal complex 398 (CC398) are a fascinating subject of interest; since they emerged in the human clinic without any obvious or understandable reasons. Strains from this lineage were only found as livestock colonizers and totally absent from the human clinic until 2007. Thereafter, cases of severe infections were increasingly reported in humans in contact with livestock and finally, CC398 are now responsible for infections even in patients without contact with animals. Annual survey programs allowed our group to observe a constant increase in the prevalence of CC398 isolates as etiologies of severe infections, whereas the current period shows a general decrease in multi-resistant S. aureus prevalence.Analysis of whole genome of different CC398 isolates revealed quite homogeneous sequences except for prophage content. We obtained clear evidences that isolates have acquired during the last decade, genetic features contributing to adaptation and virulence through integration of prophages. Series of phenotypic determinations allowed us to demonstrate that acquired mobile elements modulated i) interaction and adhesion with host tissues, ii) intracellular uptake and survival in a protected niche and iii) genome plasticity such as transformation and transduction. Interestingly, bacterial adhesion factors appear regulated at the transcriptomic level due to the presence of prophages and this is accompanied by an increased bacterial virulence. We showed that transcription alteration of bacterial adhesins contributing to virulence is mediated through an effect on saeRS transcription level. In addition, we obtained stable lysogens of these CC398 borne prophages in other S. aureus lineages present in the veterinary and human clinics. Crucial clinical questions emerged from these observations especially regarding further potential evolution toward a virulent and multi resistant phenotype. The accompanying issue relies on the eradication of these isolates by using lytic phages (e.g. phage therapy) that relieves a particular importance considering prophage mobility and possible transfer of genes affecting virulence or resistance in commensal flora of treated patients. The two major aims of this proposal are the identification of genes from the lysogenic phages i) interacting with saeRS and other actors of pathogenicity, contributing to increased bacterial virulence and ii) mediating evolution of the lineage. We will use molecular tools as well as phenotypic tests available in my laboratory to identify these genes and clarify mechanisms they triggered. The success of this proposal should contribute not only to clarify the molecular mechanisms responsible for the evolution of colonizers to highly virulent strains.
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