Impact of the Stringent Response on Virulence of Enterobacter cloacae (IRENE)

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Impact of the Stringent Response on Virulence of Enterobacter cloacae (IRENE)

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Offer DescriptionThe Marie S. Curie Postdoctoral Fellowship (MSCA-PF) programme is a highly prestigious renowned EU-funded scheme. It offers talented scientists a unique chance to set up 2-year research and training projects with the support of a supervising team. Besides providing an attractive grant, it represents a major opportunity to boost the career of promising researchers.The INSERM/ Université de Rennes Unit U1230 , is thus looking for excellent postdoctoral researchers with an international profile to write a persuasive proposal to apply for a Marie S. Curie Postdoctoral Fellowship grant in 2024 (deadline of the EU call set on 11 September 2024). The topic and research team presented below have been identified in this regardResearch field: Life Sciences (LIF), MicrobiologyKeywords: Bacterial stress response ; second messenger ; bacterial alarmone ; (p)ppGpp ; E. cloacae complex ; host-pathogen interactionResearch project descriptionEffectively responding to environmental changes is crucial for pathogenic bacteria to ensure their survival and proliferation within their host. One of the most characterized bacterial stress responses is the stringent response, which is mediated by the guanosine tetra- or pentaphosphate, collectively referred to as (p)ppGpp alarmone. These hyperphosphorylated guanosine transiently alters bacterial physiology by targeting essential processes, including translation, transcription, and DNA replication. Tight regulation of this alarmone is critical for optimizing bacterial growth rates in response to changing environmental conditions.In agreement with its central role in bacterial adaptation, (p)ppGpp has been integrated by many pathogens into their regulatory networks to control the expression of virulence factors. When the enteric pathogen Salmonella enterica serovar Typhimurium (henceforth referred to as Salmonella) reaches the intestinal epithelium, production of (p)ppGpp promotes the expression of a type III secretion system (T3SS), SPI-1, required to invade non-phagocytic enterocytes by bacterial-mediated endocytosis. After crossing of the epithelial barrier, Salmonella is phagocytosed by intestinal immune cells such as macrophages. Remarkably, production of (p)ppGpp in response to the intracellular environment is required for the expression of a second T3SS, SPI-2. This (p)ppGpp-dependent machinery is critical to reprogram the macrophages into a favorable niche for the proliferation of intracellular Salmonella. In agreement with the function of (p)ppGpp in the expression of virulence programs associated with invasion (SPI-1) and intracellular proliferation (SPI-2), (p)ppGppdeficient strains are attenuated in infection models.While the downstream consequences of (p)ppGpp accumulation in the success of the infection has been demonstrated in pathogens like Salmonella, it remains largely uncharacterized in most top-priority pathogens (ESKAPE). For example, our understanding of (p)ppGpp metabolism and its impact on virulence of Enterobacter cloacae complex (henceforth referred to as Ecc) remains unknown due to the scarcity of research conducted in this area.Although Ecc is naturally present as a commensal in the human and animal gut microbiota, it is responsible for hospital-acquired infections and currently poses a significant challenge in clinical settings. Notably, this opportunistic pathogen is often associated with a multidrug-resistant phenotype, primarily due to its propensity to acquire numerous mobile genetic elements containing resistance and virulence genes. Assessing how (p)ppGpp metabolism impacts the virulence of Ecc might bring some important insights into the physiopathogenicity of this bacterium.To gain insights into the role of (p)ppGpp in Ecc, the Postdoctoral fellow will conduct RNAseq on both wild-type and (p)ppGpp-deficient strains to elucidate how (p)ppGpp regulates genes associated with Ecc virulence. Then, the Postdoctoral fellow will assess the importance of (p)ppGpp and its targets in infection models. This work aims to establish the foundation of (p)ppGpp function in the virulence of Ecc, which is essential to understand the overall disease progression.Relevant references1. Irving SE, Choudhury NR, Corrigan RM. The stringent response and physiologicalroles of (pp)pGpp in bacteria. Nat Rev Microbiol. 2021 Apr;19(4):256-271. Epub2020 Nov 4. PMID: 33149273.2. Ronneau S, Hallez R. Make and break the alarmone: regulation of (p)ppGppsynthetase/hydrolase enzymes in bacteria. FEMS Microbiol Rev. 2019 Jul1;43(4):389-400. PMID: 30980074.3. Davin-Regli A, Lavigne JP, Pagès JM. Enterobacter spp.: Update on Taxonomy,Clinical Aspects, and Emerging Antimicrobial Resistance. Clin Microbiol Rev.2019 Jul 17;32(4):e00002-19. PMID: 31315895SupervisorThe Postdoctoral Fellow will be supervised by Prof. Vincent CATTOIR, who is Professor of Clinical Microbiology at the Univ. of Rennes 1, Director of in the Inserm U1230, Head of the Bacteriology department at the Univ. Hospital of Rennes and the Director of the National Reference Center for enterococci. He studies genetic and biochemical mechanisms of antimicrobial resistance, both in Gram-positives and Gram-negatives. His experimental approaches are microbiological assays for antimicrobial resistance, NGS-based approaches (comparative genomics, transcriptomics) and several animal models of infection by E. cloacae complex. He is author of
220 publications in peer-reviewed journals (h-index=51, i10 index = 149;
10,200 citations), 1 book, 28 book chapters, and presented
80 invited keynote lectures and co-authored
230 conference abstracts.Relevant references1. Guérin F, Gravey F, Reissier S, Penven M, Michaux C, Le Hello S, Cattoir V.Temocillin Resistance in the Enterobacter cloacae Complex Is Conferred by aSingle Point Mutation in BaeS, Leading to Overexpression of the AcrD EffluxPump. Antimicrob Agents Chemother. 2023 Jun 15;67(6):e0035823. Epub 2023May 17. PMID: 37195180.2. Cattoir V. The multifaceted lifestyle of enterococci: genetic diversity, ecology and risks for public health. Curr Opin Microbiol. 2022 Feb;65:73-80. Epub 2021 Nov 9. PMID: 34768106.3. Gravey F, Cattoir V, Ethuin F, Fabre L, Beyrouthy R, Bonnet R, Le Hello S, Guérin F. ramR Deletion in an Enterobacter hormaechei Isolate as a Consequence of Therapeutic Failure of Key Antibiotics in a Long-Term Hospitalized Patient. Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00962-20. PMID: 32778545.DepartmentThe Inserm unit U1230 headed by Prof. Vincent CATTOIR is a trans-disciplinary and translational research structure ( ), relying on tight trans-disciplinary interactions between several scientific fields including, microbiology, biochemistry, molecular and cell biology, chemistry and the clinic. More specifically, we unravel general mechanisms by which human pathogens regulate gene expression during infection, and try understanding transition between colonization and infection. Our model systems include (but are not limited to) S. aureus, E. faecium and E. cloacae complex. We use animal models of carriage, local and systemic infections combined with powerful genetic and molecular technologies. We have state of the art in house facilities hosted by Biosit ( ). Prof. Vincent CATTOIR is also Director of the National Reference Center for enterococci and part of the Bacteriology laboratory, giving him direct access to a large amount of clinical isolates from France and the 1,800-bed University Hospital of Rennes, respectively. Different national grants have recently been obtained (INCa 2015-2018 [partner], FRM 2017-2020 [PI], FRM 2018-2022 [PI], ANR 2019-2023 [partner], ANR PPR 2021-2026 [PI]).RequirementsResearch Field Biological sciences » Other Education Level PhD or equivalentSkills/Qualifications-Specific skill requirements: Bacteriology, Bacterial genetics, Transcriptomics (RNA seq), Bioinformatics-Required languages: English (French is recommended but not mandatory)-Publications: at least one first author publication.Languages ENGLISH Level ExcellentAdditional InformationEligibility criteriaAcademic qualification: By 11 September 2024, applicants must be in possession of a doctoral degree, defined as a successfully defended doctoral thesis, even if the doctoral degree has yet to be awarded.Research experience: Applicants must have a maximum of 8 years full-time equivalent experience in research, measured from the date applicants were in possession of a doctoral degree. Years of experience outside research and career breaks (e.g. due to parental leave), will not be taken into account.Nationality & Mobility rules: Applicants can be of any nationality but must not have resided more than 12 months in France in the 36 months immediately prior to the MSCA-PF call deadline on 11 September 2024.Selection processWe encourage all motivated and eligible postdoctoral researchers to send their expressions of interest through the EU Survey application form ( ), before 5th of May 2024. Your application shall include:

• a CV specifying: (i) the exact dates for each position and its location(country) and (ii) a list of publications;

• a cover letter including a research outline (up to 2 pages) identifying theresearch synergies with the project supervisor(s) and proposed researchtopics described above.

Estimated timetableDeadline for sending an expression of interest5 May 2024Selection of the most promising application(s)May – June 2024Writing the MSCA-PF proposal with the support of the above-mentioned supervisor(s)June – September 2024MSCA-PF 2023 call deadline13 September 2024Publication of the MSCA-PF evaluation resultsFebruary 2025Start of the MSCA-PF project (if funded)May 2025 (at the earliest)Website for additional job detailsWork Location(s)Number of offers available 1 Company/Institute The Inserm unit U1230 Country France GeofieldWhere to apply WebsiteContact State/ProvinceBretagne CityRennes WebsiteStreetVillejean – Bâtiment 5 – Etage 2 – Rue du professeur Léon Bernard Postal Code35043 E-Mailcontact@2PE-bretagne.euSTATUS: EXPIRED

Expected salary

Location

Rennes, Ille-et-Vilaine

Job date

Sun, 31 Mar 2024 04:58:13 GMT

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