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Complement resistance mechanisms by multi-drug resistant Klebsiella pneumonia

  • Full or part time
    Prof S Rooijakkers
    Prof A Blom
  • Application Deadline
    Sunday, November 10, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

The aim of this project is to characterize complement evasion molecules in the opportunistic bacterium Klebsiella pneumoniae (K. pneumoniae) where carbapenem-resistance grew from 1.6% to 10.4% in 10 years. In order to survive in the human body, bacteria have evolved mechanisms to avoid clearance by the immune system. For instance, our lab discovered that the prominent Gram-positive pathogen Staphylococcus aureus secretes a number of proteins that block critical steps in the complement cascade [Rooijakkers, Nat. Immunol. 2015, 2019]. Only little is known about the mechanisms that K. pneumoniae uses to withstand killing by complement attack.
This project has two main objectives:

1) Identify Klebsiella proteins (either secreted or expressed in the outer membrane) that interfere with complement activation. To this end, we will employ an efficient phage display library (running in the lab) for identification of bacterial secreted virulence factors that can be screened against various complement targets. Also, we already have a list of potential ‘immune evasion’ candidates. All protein candidates will be produced recombinantly and subsequently tested in a variety of functional assays (bacterial killing in serum, flow cytometric-based viability assays, neutrophil phagocytosis, complement deposition assays etc). For membrane protein candidates, we will generate deletion mutants or knock-ins of the relevant genes in bacterial strains to assess their relevance in context of the whole organism.

2) Decipher how complement-resistant Klebsiella strains withstand direct killing by the complement system. The complement system can directly kill Gram-negative bacteria by formation of a large, ring-structured, multi-protein Membrane Attack Complex (MAC). The MAC inserts into the bacterial outer membrane and, through an unknown mechanism, causes permeation of the bacterial inner membrane [Heesterbeek, EMBO J, 2019]. Unpublished data from our lab suggest that some Klebsiella strains specifically resist the lethal inner membrane damage. We will use transposon library mutagenesis and RNA sequencing approaches to study how these bacteria protect from MAC-mediated inner membrane damage.

General description of your individual PhD-schedule:

• Your main university will be Utrecht University/ University Medical Center Utrecht (Netherlands) with Prof. Rooijakkers as supervisor.
• You will have a 6-months research secondment at Lund University (Sweden) with Prof. Blom as supervisor, where you continue to scientifically work on your thesis project.
• You will have a 1-month clinical training at Tirol Kliniken Innsbruck (Austria).
• You will have a 1-month entrepreneur training at Statens Serum Institut (Copenhagen, Denmark).
• You will finally receive a PhD issued by Utrecht University and Lund University if you fulfil the respective requirements.

Application

Please visit http://www.corvos.eu for application and more information on the PhD program. You have to submit: Application Form (see http://www.corvos.eu), CV, Master/MD/Diploma document, Abstract of Master/MD/Diploma thesis. Selected candidates will be invited for a personal interview to Innsbruck on 03rd/04thJan or 09thJan2020.

Requirements:

We are looking for highly qualified and motivated aspiring PhD students from any nationality with an open-minded and very enterprising personality, capable of working in collaborative and integrated research groups. Ideal candidates should possess a good scientific drive and a strong motivation to succeed.

•You have a full study completing degree (Master, Magister, Diploma, MD) in medicine, natural sciences or related disciplines until March 2020
•You are an Early Stage Researcher (ESR) – you either just finished your studies, or you have worked less than 4 years as an employee in the biomedical sector after obtaining your degree
•You have to show academic excellence, scientific potential, flexibility, motivation and suitability for the research project
•You have the willingness to stay abroad for 3 years from your current residence and willingness to travel through Europe
•You comply with the mobility rule for Marie Sklodowska Curie ITN fellows – Researchers must not have resided or carried out their main activity (work, studies, etc.) in the country of the recruiting university for more than 12 months in the 3 years immediately before the recruitment date. This will be thouroughly checked.

Funding Notes

The Marie Sklodowska-Curie project CORVOS, for COmplement Regulation and Variations in Opportunistic infectionS, is funded as an Innovative Training Network (ITN) – European Joint Doctorate (EJD). Its focus lies on education of young scientists in the field of complement in opportunistic infections. This interdisciplinary doctoral program is supported by 10 European universities, 2 research institutes, 3 biomedical companies and 3 hospitals. The PhD students will have enhanced career perspectives in the academic and non-academic sectors through international, interdisciplinary and inter-sectoral mobility combined with an innovation-oriented mind-set. Visit View Website to see all the benefits that you will have as CORVOS PhDstudent.

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