Open PhD Projects
The following PhD projects are available in 2025 (earliest possible start in May 2025)
The epithelial cells of the gastrointestinal (GI) tract are in constant contact with microbial products and have to balance tolerance of commensals and defense against pathogens. To sense the microbial world, epithelial cells are equipped with innate immune receptors, such as toll-like receptors or inflammasomes. Our group uses adult stem cell derived organoids to better understand epithelial innate immunity and the host response to infection. Organoids are 3-dimensional, primary cell cultures. Analyzing human and murine GI organoids, we found that innate immune receptor expression is highly organized in the GI tract: Each segment of the GI tract expresses a specific set of innate immune receptors. We now wonder, how this spatial organization develops and how this impacts the defense against pathogens. In this project, we will use CRISPR/Cas9-mediated genetic modification of human GI organoids to analyze the impact of specific genes on innate immune receptor expression. We will further use infection models, such as EPEC infection of human intestinal organoids, to better understand the importance of innate immune recognition in infection.
References:
DOI: 10.1136/gutjnl-2019-319919
Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis, is the leading cause of death by a single infectious agent in the world. The granuloma, the central structure of tuberculosis, is an aggregate of macrophages and other immune cells that forms around the infecting mycobacteria. This structure has been recognized for more than 100 years as a critical pathological outcome of tuberculosis infection and has also recently been recognized as a major limiter of antibiotic killing and clinical outcome of this infection. We have found that the granuloma, driven by type 2 immune signals, leads to a bona fide epithelialization event within the macrophages that is necessary for the formation of this structure. The goal of this project is to characterize the molecular underpinnings of the granuloma. To study these responses, we use in vivo modeling in zebrafish infected with Mycobacterium marinum, a close relative of M. tuberculosis that has effectively translated into human findings, in conjunction with mechanistic in vitro cell culture approaches and human patient samples. This project will follow up on screening efforts in the lab, using cell culture and in vivo studies to mechanistically unpack the transcriptional rewiring driving this structure and the functional outcomes in mycobacterial pathogenesis.
Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that are deeply integrated in the regulation of tissue function. Based on our data (Gronke, Nature 2019; Guendel, Immunity 2020; Diefenbach, Immunity 2020; Witkowski, Nature 2021; Biniaris, Nature 2024), we hypothesize that ILCs regulate organ growth and regeneration. In this project, we are exploring the role of ILCs and of IL-22 for liver regeneration. Our preliminary data show that liver regeneration is dependent on IL-22. We have already obtained a high resolution scRNAseq atlas of the regenerating liver that reveal molecular networks of IL-22-dependent regeneration. Three key questions will be addressed:
- How is IL-22 production regulated during liver regeneration?
- Which key regenerative pathways in hepatocytes are controlled by IL-22?
- Can IL-22 be used to promote liver regeneration? To address these questions, we use CRISPR/Cas9-driven lineage tracing/barcoding in combination with high dimensional single cell genomics.
Funding: ERC, DFG, BMBF
Pertussis, or whooping cough, is a highly contagious respiratory disease resulting predominantly from infection with the bacterium Bordetella pertussis. Although vaccine-preventable, the disease still exacts a heavy toll in low-income countries and has re-emerged in high-income countries with sustained high vaccination coverage. A central problem in pertussis epidemiology is the lack of consensus on the burden of pertussis infections, especially asymptomatic infections. The proposed project will aim to estimate the real burden of pertussis infections using mathematical modeling and statistical inference. To this end, the student will develop a new generation of mathematical models that simultaneously capture transmission and serological dynamics, allowing for integration and evidence synthesis of case reporting incidence data and seroprevalence data. The project will build on ongoing collaborations of the lab with leading pertussis researchers in Denmark, the UK, and the US.
The persistence of malaria parasites in hosts without symptoms is vital in regions with seasonal transmission interruptions, where Plasmodium falciparum bridges wet seasons months apart. During the dry season, infected erythrocytes exhibit extended circulation with reduced cytoadherence, increasing the risk of splenic clearance of infected cells and hindering parasitaemia increase. What enables parasite persistence for long periods of time is not fully understood. We will investigate, with experiments done immediately in Berlin and in Bamako, the molecular host parasite interaction that allow efficient binding of P. falciparum infected erythrocytes in clinical cases in the wet season versus the inefficient counter part of asymptomatic infections in the dry season. Specifically, we will examine binding of iRBCs collected in the wet and dry season to human endothelial cells, determine the inhibitory effect of plasma collected longitudinally from the wet into the dry season and how it affects parasite cytoadhesion to human endothelial cells, and define the variant surface antigens expressed by P. falciparum infected erythrocytes with varying cytoadhesion abilities in the dry and the wet season.
The ability of the malaria parasite Plasmodium to adopt specialised shapes for each stage of its life cycle depends on its microtubule cytoskeleton. While it is generally assumed that microtubules are essential for the structural integrity of Plasmodium, we lack a direct link between the mechanical properties of Plasmodium microtubules and how they contribute to the mechanics of the parasite. Furthermore, it remains unknown whether and how microtubule inner proteins (MIPs) contribute to microtubule stability and the parasite’s mechanical properties. Therefore, the project proposes to use a combination of bottom-up and top-down approaches (protein expression, high-resolution optical microscopy, advanced biophotonics) to understand how the mechanical and material properties of various Plasmodium stages emerge. The aim is to gain a quantitative picture of how Plasmodium uses an evolutionarily conserved mechanism for the extraordinary stabilisation of its microtubule cytoskeleton and how this contributes to the overall mechanics of the parasite to confer cellular form and function.
Neutrophils excel at seeking out and destroying pathogens. They quickly migrate to sites of infection, where they deploy multiple antimicrobial mechanisms, including phagocytosis, degranulation and release of neutrophil extracellular traps (NETs). Fine-tuning of neutrophil responses is crucial to health: impaired responses can lead to chronic infections, while excessive activation contributes to autoimmunity and inflammatory disease. An essential mechanism permitting versatile neutrophil responses is dynamic remodeling of microtubule-based structures, however this remains poorly understood. This project will aim to characterize the composition, distribution and regulation of microtubules in neutrophils engaging in migration, degranulation and NETosis. We will investigate primary human neutrophils and utilize proteomics, live cell imaging, advanced biophysics and CRISPR/Cas9 genome editing to understand how microtubule regulation leads to optimal neutrophil antimicrobial responses.