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Subject of the thesis

Exploring two partner secretion in virulence of Gram-negative pathogens

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Published on 10 March 2020

Summary of the project
Many Gram-negative bacteria, pathogens for humans, use toxins for host cell manipulation. Two Partner Secretion systems (TPS) allows the export of high molecular weight secreted proteins (160 kDa - 400 kDa) across the outer membrane by a cognate outer membrane protein. TPSs are responsible for diverse functions from pore formation into the host-cell membrane to adhesion of the bacteria. This project will built on our previous studies on Pseudomonas aeruginosa TPS toxin Exolysin. Exolysin-like proteins with divergent C-terminal sequences, which carry the activity functions, were found in different Pseudomonas species. We will explore their structure – function relationship by using approaches ranging from biochemistry to cellular and virulence tests in vivo on different models, such as Drosophila and Galleria. We will also investigate non-exolysin TPSs in P. aeruginosa. Indeed, in addition to Exolysin, P. aeruginosa clinical strains encode five more TPSs, including a filamentous hemagglutinin (FHA)-like adhesin, PdtA, whose exact role in virulence is still obscure. We propose to study the function and structure of PdtA, in particularly, and to explore its immunogenic properties. Indeed, FHA proteins are highly immunogenic and may be used in active immunization, as demonstrated in Bordetella pertussis.

Keywords
bacterial toxins, host-pathogen interactions, secretion, anti-virulence

Applicant profile
microbiology, genetics with notions of biochemistry

Recent publications of the team
Trouillon J, Sentausa E, Ragno M, Robert-Genthon M, Lory S, Attrée I, Elsen S. 2020. Species-specific recruitment of transcription factors dictates toxin expression. Nucleic Acids Res. 2020 Jan 11. pii: gkz1232. doi: 10.1093/nar/gkz1232.
Ngo TD, Plé S, Thomas A, Barette C, Fortuné A, Bouzidi Y, Fauvarque MO, Pereira de Freitas R, Francisco Hilário F, Attrée I, Wong YS, Faudry E. 2019. Chimeric Protein-Protein Interface Inhibitors Allow Efficient Inhibition of Type III Secretion Machinery and Pseudomonas aeruginosa Virulence. 2019. ACS Infect Dis. 5(11):1843-1854. doi: 10.1021/acsinfecdis.9b00154.
Liebl D, Robert-Genthon M, Job V, Cogoni V and Attrée I. 2019. Baseplate component TssK and spatio-temporal assembly of T6SS in Pseudomonas aeruginosa. Frontiers in Microbiology. doi: 10.3389/fmicb.2019.01615.
Sentausa E, Basso P, Berry A, Adrait A, Bellement G, Coute Y, Lory S, Elsen* S, and Attrée* I. 2019. Insertion sequences drive the emergence of a highly adapted human pathogen. Microbial Genomics. doi: 10.1099/mgen.0.000265.
Basso, P., Ragno, M., Elsen, S., Reboud, E., Golovkine, G., Bouillot, S., Huber, P., Lory, S., Faudry, E. and Attree, I. (2017) Pseudomonas aeruginosa Pore-Forming Exolysin and Type IV Pili Cooperate To Induce Host Cell Lysis. mBio, 8.
Reboud, E., Bouillot, S., Patot, S., Beganton, B., Attree, I. and Huber, P. (2017) Pseudomonas aeruginosa ExlA and Serratia marcescens ShlA trigger cadherin cleavage by promoting calcium influx and ADAM10 activation. PLoS Pathogens, 13, e1006579.
Elsen, S., Huber, P., Bouillot, S., Coute, Y., Fournier, P., Dubois, Y., Timsit, J.F., Maurin, M. and Attree, I. (2014) A type III secretion negative clinical strain of Pseudomonas aeruginosa employs a two-partner secreted exolysin to induce hemorrhagic pneumonia. Cell Host & Microbe, 15, 164-176.

More
PhD supervisor and contact: Ina Attrée
Research institute: IRIG
Laboratory: BCI, UMRS 1036
Research team: Bacterial Pathogenesis and Cellular Responses (PBRC)

GRAL PhD funding includes 3 years of salary (gross salary: 1768.55 € per month) and 10,000€ of bench fees per year. Candidates must directly contact the PhD supervisor(s) to apply.

Schedule
Deadline of the call for PhD projects applications: November 2019
Opening of the call for student applications: Mars 2020
Audition for PhD candidates: May 4th 2020 at IBS, salle des conseils (Grenoble)
Results: May 2020
Registration at Université Grenoble Alpes and start of PhD project: autumn 2020
The candidate selected by the PhD supervisor(s) must send the following documents in a unique pdf file to GRAL’s Executive Manager: Anne-Mathilde Thierry before April 26th (23:59, CET):
• The application file, filled, dated, and signed Download application file
• A cover letter (one page maximum) including ranking obtained during the 1st and 2nd year of Master
• A detailled CV
• A letter of support from the PhD supervisor(s)
• Diploma(s) and copies of academic transcripts equivalent to a 1st year of MSc (or 3-yr BSc and 1 year of MSc), translated to English (or French) if needed
• Copies of academic transcripts equivalent to a 2nd year of MSc, translated to English (or French) if needed
• Level of language proficiency (e.g. TOEIC, Bulats, etc.) if available / appropriate