The Manchot Graduate School
Molecules of Infection V (MOI-V) offers an innovative, structured training and research program in a both stimulating and interdisciplinary field of medicine and biology. Highly motivated and excellent candidates holding a MSc degree in biology, biochemistry or related subjects are strongly encouraged to apply.
The scholarship comprises inter alia a monthly allowance of 1,900 € over a period of 3.5 years as well as a budget for material expenses and financial support for the attendance of national and international conferences and for a temporary stay abroad.
12 PhD scholarships in the MOI-V Manchot Graduate School
Activities and responsibilities
Job profile:
The research program of the MOI-V Manchot Graduate School focuses on the characterization and functional dissection of selected host-pathogen interactions at the molecular level and the mechanism that control immunological responses to infectious diseases. In doing so, it follows the highly successful approach adopted in the previous funding periods for MOI-I, MOI-II, MOI-III and MOI-IV.
Qualification profile
Project 17:
The role of the purinergic receptor P2X7 for cross-presentation of antigens during poxviral infection (Prof. Dr. Ingo Drexler, Institute for Virology, HHU Düsseldorf)
Vaccinia virus (VACV) belongs to the poxvirus family and is a large dsDNA virus that replicates in the cytoplasm of the infected cell. It encodes more than 200 genes, about a quarter of which have immunomodulatory functions. The virus is an acute infectious agent and has been successfully used in the past as a vaccine for the eradication of smallpox (variola). Attenuated VACV strains such as MVA (modified vaccinia virus Ankara) are tested in clinical trials as recombinant vector vaccines against infectious diseases for their safety and immunogenicity. We have shown that cross-presentation plays an essential role for optimal cytotoxic CD8+ T cell (CTL) responses in this infection model. Cross-presentation enables cell-associated antigens from the extracellular milieu, which are normally presented on MHC class II molecules, to also be presented on MHC class I molecules. This process enables a combined and therefore more efficient CD4+ and CD8+ T cell response to various infectious agents. The investigation of the relevance of cross-presentation for the induction of T cell responses in the VACV infection model in the mouse is a central topic of the research group. In previous work we were able to show that the ability to cross-present is not only determined by the type of cell that presents, but also by the infected cell that provides the antigens. These so-called feeder cells licence bystander non-infected cells to take up the antigens and cross-present them. This process requires both, effector molecules of the innate immune system such as type I interferons as well as components of the signalling pathway for apoptosis such as the purinergic receptor P2X ligand-gated ion channel 7 (P2RX7).
As a surface receptor, P2RX7 is mainly expressed in endothelial, epithelial and immune cells. It is involved in the regulation of immune responses via cytokine release, inflammatory processes through inflammasome activation and apoptosis through regulation of mitochondrial activity. Studies show that P2RX7 is also localised intracellularly on mitochondrial structures. The absence of functional P2RX7 in infected feeder cells therefore resulted in a greatly reduced number of cross-presenting dendritic cells (DC), which contained significantly fewer virus-specific peptide/MHC-I complexes on the cell surface. The latter also explains the significantly reduced cytokine production (IFNү, TNFα) of virus-specific CD8+ T cells co-cultured with these cross-presenting DC. In this project, the cellular signalling pathways and molecular processes relevant for efficient cross-presentation will be investigated as a function of P2RX7, both in the feeder cell and in the cross-presenting DC.
The planned working program includes the investigation of metabolic processes in the feeder cell with relevance for cross-presentation depending on P2RX7, such as energy metabolism or mitochondrial activity. Colocalisation studies on the intracellular localisation of P2RX7 during infection using confocal microscopy (CLSM). Analysis of the secretome (proteins, nucleic acids) of infected feeder cells in relation to P2RX7 in the supernatant and in extracellular vesicles. Functional analysis of the vesicular fractions e.g. for cross-presentation. Further analysis of the vesicles with measurement of particle size, concentration and content (see above). Investigation of cell biological changes in the formation of EVs after infection (CLSM). Investigation of the role of the inflammasome as a function of P2RX7. Co-expression of P2RX7 in recombinant MVA for in vitro and in vivo analyses after vaccination in the mouse model.
We offer
The dissertation projects are cross-linked both in content and methodology. Within the scope of the MOI-V qualification program, lectures, seminars and a lab rotation will provide the PhD students with thorough insight into the infection biology of the three big pathogen groups of viruses, bacteria and fungi/protozoa as well as into the host’s immune response. In the course of the study program, the students will be enabled to acquire extensive professional key competences. A temporary stay abroad is an integral part of each dissertation project. Yearly MOI symposia offer a platform for presenting own research results and intensive scientific exchange. An international scientific advisory board accompanies MOI-V and supports the PhD students during their projects.
The Heinrich-Heine-University with more than 34,000 students forms the core of the university town Düsseldorf. As a full university with its five faculties law, economics, humanities, medicine, and mathematics & natural sciences, the HHU promotes close interdisciplinary cooperation on the regional, national and international scale. The HHU has, already for several times, been awarded with the certificate “TOTAL E-Quality”.