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Characterization of C5aR2 expression and function in Toxoplasma gondii infection

  • Full or part time
    Prof J Koehl
    Prof D Wilflingseder
  • Application Deadline
    Sunday, November 10, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

Toxoplasma gondii (T. gondii) is a widespread obligate intracellular protozoan parasite. It is of major medical importance during pregnancy and in immunocompromised individuals. The parasite is sensed by complement resulting in the fixation of C3 cleavage fragments. The role of the C5a/C5a receptor (C5aR) axes has not been addressed. The Köhl laboratory observed increased parasite load in the brain associated with increased mortality in C5ar1-/- mice. Mechanistically, C5aR1 activation controlled early T. gondii infection by IL-12 production from splenic DCs, which is crucial for IFN-γ production from NK cells and subsequent iNOS expression in the brain. Surprisingly, we found that NK cells express C5aR2 but not C5aR1. In vitro experiments suggest that C5aR2 activation regulates IL-12/IL-18-mediated IFN-γ production from NK cells. We hypothesize that C5aR2 activation on NK cells controls early T. gondii infection given the importance of NK cell activation during this infection phase. To test this hypothesis, the student will monitor C5aR2 expression during early parasite infection using floxed tdTomato-C5aR2 knock-in mice generated in the Köhl lab (Karsten et al. J. Immunol 2017). Also, s/he will infect C5ar2-/- and wildtype mice, determine disease progression, assess systemic and splenic IL-12 cytokine family and IFN-γ expression in DCs and NK cells. Further, s/he will infect NK cell-specific C5aR2-deficient mice to specifically define the role of C5aR2 on NK cells in this infection model. Since the interaction of NK cells with DCs is of major importance for NK cell activation, the student will assess the role of C5aR2 on DCs for DC-mediated activation of NK cells while staying 6 months in our partner lab in Innsbruck (AT). Currently, no monoclonal antibodies (mAbs) are available that reliably stain and/or neutralize C5aR2. Thus, the student will generate mAbs against C5aR2 in Lübeck (DE) and test their functional properties in vitro and in vivo models. During the 6 months visit of Hycult Biotech (NL), the student will exploit the commercial value of such mAbs and learn to produce C5aR2-specific mAbs in large quantities and couple them with fluorochromes or enzymes for their use in different application fields.

General description of your individual PhD-schedule:
• Your main university will be University of Lübeck (Germany) with Prof. Köhl as supervisor.
• You will have a 6-months research secondment at Medical University of Innsbruck (Austria) with Prof. Wilflingseder as supervisor, where you continue to scientifically work on your thesis project.
• You will have a further 6-months research secondment at Hycult Biotech (Uden, Netherlands) where you will generate and characterize C5aR2-specific mAbs.
• You will have a 1-month clinical training at University Hospital Helsinki (Finland).
• You will have a 1-month entrepreneur training at Hycult Biotech.
• You will finally receive a PhD issued by University of Lübeck and Medical University of Innsbruck 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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