We have 6 PhD positions available
- Lipid dys-homeostasis and the control of bacterial infection (Supervisor: Günter Weiss)
Lipid homeostasis undergoes subtle chances during infectious diseases, which also reflects the as yet underestimated role of lipids in host pathogen interaction. While lipid homeostasis and cellular lipids composition are of importance for cellular membrane composition, metabolism and immune function of macrophages including phagocytosis or chemotaxis, lipids or its catabolic produces as propionyl-CoA can serve as nutrients or virulence factors for intracellular bacteria. Thus, alterations in lipid homeostasis and lipid anabolic/catabolic pathways in macrophages play decisive role in host-pathogen interaction. We hypothesize that alterations of cellular and systemic lipid metabolism alter the course of infections with the intracellular bacterium Salmonella typhimurium and the extracellular bacterium Escherichia coli by impacting on specific host immune responses. Building up on our expertise in lipid research and on promising results from our group this project will first employ, murine and human monocytic cell lines as well as primary cells to study the effects of altered extracellular lipid composition on the course of infection and immune response with the intracellular bacterium S. typhimurium and E.coli using protocols established in our laboratory. Along this line the impact of bacteria on lipid homeostasis and trafficking in monocytes will be analysed. Targeted deletion of critical lipid homeostasis genes in vitro (CRISP9CAS) and in vivo (Alb and LysMCre) as well as specific mouse models of hyperlipidemia will further scrutinize the importance of specific lipid pathways in monocytes for the control of infection and the control of associated immune responses by applying classical analytical and molecular methods along with functional and life imaging analyses of specific host pathogen interactions.
- Complement and complement-based therapy in mucormycete infection (Supervisors: Reinhard Würzner & Prof. Cornelia Speth)
Mucormycosis, the infection with the fungal pathogens mucormycetes, induces significant morbidity and mortality in immunocompromised patients; the antifungal treatment of affected patients is still suboptimal. An immune-based therapeutic strategy might improve the outcome of affected patients.
The complement system, a putative candidate for such a therapy, is a fast-acting first-line player of the innate immunity and thus might represent an efficient defence also against mucormycetes. However, its precise capacity to detect and to bind to the fungi as well as its precise role in the pathogenesis of mucormycosis has not been studied yet. For that reason this PhD project aims to improve current knowledge about the role of complement in invasive mucormycosis and to develop new complement-based therapeutic approaches to avoid rapid fatal outcome of invasive mucormycosis. A broad spectrum of microbiological and immunological methods will be used in this project.
- Host factors involved in coli-induced haemolytic uraemic syndrome (eHUS) (Supervisors: Prof. Reinhard Würzner & Prof. Dorothee Orth-Höller)
Enterohaemorrhagic E. coli (EHEC)-associated haemolytic uraemic syndrome (eHUS) is a disease which affects only 5-15% of human beings after an infection with EHEC bacteria. eHUS has therefore being regarded as opportunistic complication of an EHEC infection, although the molecular bases originating in host defence that are facilitating severe disease are not known yet. One of the host factors is complement, interacting with at least two EHEC virulence factors. Allotypes of complement regulatory proteins have also been found associated with eHUS, and complement inhibiting therapy is used in eHUS cases. Young children and boys (in particular in Argentina) are especially affected. On the pathogen side two forms of the circulating toxin and main virulence factor Stx2a have been very recently described, a cleaved and an uncleaved version and it is not clear which versions occur in the different pathophysiological stages.
The following hypotheses should be tackled within this PhD thesis:
- The young age of most patients and the preference of boys suffering from eHUS are not (exclusively) explained by the higher exposure (e.g., pet zoos) or behavioural patterns, respectively, but by different molecular interactions between Stx2a and host factors, including gender, age and immune status, especially complement.
- There is an additional role for iron, which has a negative effect on neutrophil function in many infections.
- The two forms of the toxin may act in different pathophysiological stages.
The PhD student will use the established methods on Stx2 binding to blood cells using “biomaterials” from old and young, male and female patients, at high or low iron concentrations. Furthermore, both types of toxins will be used in these studies.
- LymphARTcis – a unique approach to study HIV-1 ´in vivo´(Supervisors: Prof. Günter Weiss & Prof. Doris Wilflingseder)
The immune response to infections consists of complex interplays between pathogens (viruses, bacteria, fungi), innate and adaptive immunity and aims in eradication of the pathogen with least damage to the host. Thereby, the immune system has evolved to resist a wide variety of invading pathogens, and further specialized in vertebrates with the development of highly organized secondary lymphoid tissues (LT: lymph nodes [LN], spleen, tonsils). Despite these sophisticated mechanisms, some infectious agents, i.e. HIV-1 or tuberculosis, developed mechanisms to resist and even exploit the host immune response and become persistent. For retroviral infection studies, non-human primates and humanized mouse models represent the animal models of choice. Both models exhibit limitations: current simian models, though robust and highly homologous, are often expensive and difficult to maintain and there are efforts to replace the use of non-human primates in biomedical research due to ethical and scientific reasons (´Three Rs´ concept of Replacement, Refinement and Reduction of animal use for experimental purposes). Humanized mouse models are further used for retroviral infection studies, but especially for our aims with respect to T cell selection/activation these models are not suitable due to lack of HLA class I and II in the murine system. Additionally, these mouse models are short-lived and do not allow to study chronic/opportunistic infections.
As an alternative approach we therefore want to design a 3-dimensional T cell zone of a human LN during the project period to further dissect host-pathogen interactions and immunological processes during viral infection. Human 3D systems are superior to cell culture monolayers, which lack the whole organ complexity and show limitations respecting long-term cultures. The in vitro 3D system, engineered during the project period, will allow to exactly characterise the function of different DC subsets and opsonization patterns in immune response initiation against retroviral infections. Analyzing dendritic cell (DC)/T cell interactions enrolling the opsonization pattern of HIV-1 in more detail in a setting close to reality is a key issue in the field of HIV pathogenesis. The translational aspect or commercial exploitation of the developed technologies is a long term aim and novel findings in this project are potentially also transformed to other scientific areas or industrial applications, i.e. drug screening or vaccination technologies.
- Functional characterization of fungal genes involved in iron homeostasis as targets for antifungal therapy (Supervisors: Hubertus Haas & Prof. Florentine Marx-Ladurner)
For virtually all organisms iron is essential, but toxic in excess. Adaptation to iron starvation includes down-regulation of iron-consumption and up-regulation of iron uptake. We have previously demonstrated that siderophore-mediated iron acquisition and regulatory adaptation to iron starvation by the transcription factors HapX, SrbA and LeuB are crucial for virulence of the most common human mold pathogen, Aspergillus fumigatus.
Via Genome-wide transcriptional profiling, we have identified genes that are regulated by iron including structural as well as putative regulatory genes. The respective gene products are potentially involved directly in iron homeostasis or in coordination of metabolic pathways with the cell´s iron status. The aim of this project is the functional characterization of these genes including their role in virulence. The detailed insight into fungal virulence determinants will be instrumental for improvement of antifungal therapy.
- 5-flucytosine in antifungal therapeutics (Supervisor: Fabio Gsaller, PhD)
In excess of 1.5 million deaths are caused by fungal infections each year. More than one third result from invasive and chronic mould infections, predominantly by the major human mould pathogen Aspergillus fumigatus.
The current therapeutic arsenal for the treatment of invasive fungal infections comprises only four classes of antifungal agents - triazoles, polyenes, echinocandins and nucleobase-analogs.
The clinical use of 5-flucytosine (5FC) for the treatment of aspergillosis, the only member of antifungal nucleobase-analogs, is limited and further reduces treatment options, which illustrates an additional challenge in the combat against this life-threatening disease. Our recent work uncovering the major cause of intrinsic 5FC tolerance in A. fumigatus and the requirement for novel therapeutic strategies strongly encourages further investigation of the 5FC metabolic pathway and the development of novel therapeutics to improve the potential of this compound in antifungal therapy.
Within this project we apply a combination of microbiological, genetic and biochemical tools as well as 5FC treatment modelling to elucidate genetic factors that play pivotal roles in 5FC activity. Simultaneously, their contribution to resistance development will be assessed. Outcomes of this project will help to design novel strategies for the optimal application of this compound.
The candidate’s work place will be the Division of Molecular Biology, which is part of the Biocenter, a collaborative research institution at the Medical University of Innsbruck facilitating exchange in technical and scientific expertise among various fields of science.
• Individual supervision and monitoring (students have their individual thesis steering committee)
• A highly structured HOROS-specific educational programme
• Funded research exchange with international laboratories
• Retreats and social activities
• Guaranteed salary as suggested by the Austrian Science Fund for the proposed 3-years
• Health insurance and social benefits
• State-of-the art facilities and resources
Join HOROS: Requirements
The entry requirement is a full study completing degree (Master, Magister, Diploma, MD) in medicine, natural sciences or related disciplines. Medical or Science students have to show academic excellence, scientific potential, flexibility, motivation and suitability for the research project.
Please submit the following documents by email
(document in PDF format using "lastname_firstname.pdf") to email@example.com
• Filled application form
• Master/MD diploma
• Recommendation letter
• Abstract of diploma/master/MD thesis
We can only accept complete applications. Incomplete applications will not be considered!
PhD students are selected on the basis of their application materials and the selected candidates will be invited to a personal interview at Medical University Innsbruck.
• Verification that the application is complete and that the applicant fulfils all requirements
• Obtaining candidate evaluations from referees
• Evaluation by HOROS faculty members and ranking of candidates based on their qualifications, research experience, and future plans
• Invitation of preselected candidates for a hearing and personal job interview in Innsbruck on 08 January 2019 (justifiable expenses for travel and accommodation will be reimbursed)
• Final selection of stipendiates
• Start of project in March 2019