Organ-specific immune-mediated inflammatory diseases (IMIDs) have a growing socio-economic impact due to their steadily increasing incidence. At least two aspects are still unclear: what immunological mechanisms restrict these diseases to one or a set of specific organs and what triggers the continuously increasing incidence, particularly in industrialized countries. Increasing exposure to harmful environmental triggers, such as pollution but also Western diet, have been suggested as potential reasons. We propose that when locally active immune cells are perturbed by harmful environmental triggers this leads to organ-specific IMIDs. Naïve CD4+ T cells have so far been considered a quasi-homogenous and inert population excluded from organs. Therefore, their contribution to organ-specific IMIDs has been overlooked. Contrary to this, there is evidence that naïve T cells circulate through organs and diversify into different subpopulations reflecting the organ they patrol. This project aims to reveal whether organ adaptation of naïve T cells in steady state is one of the key mechanisms contributing to the organization of the immune system into districts of competence - i.e., areas of inflammation. We also aim to understand whether organ-specific naïve T cells responding to harmful environmental triggers set the early premise for the development of organ-specific IMIDs. We will study this using a unique portfolio of healthy and diseased human organs in combination with multi-modal single-cell technologies to gain an unprecedented resolution in the analysis of naïve T cells. Next, we will use mouse models and 3D human cocultures to test naïve T cell function and response to environmental triggers. This project will influence the current understanding of how the activity of the immune system is adapted and distributed throughout the body, which will also push the boundary of precision medicine to consider organ-specific naïve T cells when designing future immunotherapies.

The goal of this highly multi-disciplinary and inter-sectional proposal is to develop a novel computational in-vivo MRI technique, namely Mesoscopic White-Matter magnetic resonance Imaging (MWMI). MWMI will measure 5 specific micro-scale metrics at a mesoscopic spatial resolution of about 300 μm: myelin, iron, water concentration, axonal density, and the ratio between inner and outer fiber diameter (g-ratio) - a surrogate measure for its conductance speed. Conventional quantitative MRI (qMRI), such as Diffusion Tensor Imaging, can detect but not determine the origin of microstructural changes, whereas MWMI will both detect microstructural changes and identify their origin (e.g. whether learning leads to axonal reorganization or myelination). To facilitate MWMI, 3 major methodological innovations will be developed: (a) Advanced biophysical models: Unlike existing biophysical models (e.g. axonal diameter model), which are ill posed due to the restriction to one qMRI mechanism, MWMI will combine 4 different qMRI mechanisms (relaxometry, diffusion MRI, magnetization transfer, and proton density imaging) to better condition its models. (b) Spatial integration: Novel physically-informed artifact correction methods will allow spatial integration of high-quality maps from 4 different qMRI techniques with sub-voxel accuracy. (c) Mesoscopic resolution: Unlike standard biophysical models and qMRI, the unprecedented resolution of MWMI will allow estimating micro-scale metrics within the white matter that are unbiased by partial volume effects. The pain circuit, which is a fundamental and well-described sense, will be used to demonstrate the feasibility of MWMI. Longitudinal MWMI be performed to measure micro-scale correlated of nociceptive long-term habituation in the spinal cord, the first and crucial anatomical structure associated with pain.

Chronic kidney disease (CKD) affects around 10% of the population worldwide and is associated with significant overall and cardiovascular mortality. CKD is a heterogeneous group of disorders characterized by alterations in kidney structure and function and is progressive in nature. Autoimmune diseases are a common cause of CKD and responsible for its most aggressive and progressive forms, mainly in younger patients. Autoantibodies play major pathogenic roles in most of these disorders and multiple disease-specific target antigens have been identified – circumstances that have shifted treatment strategies from largely unspecific immunosuppression towards B and plasma cell-targeted therapies. However, such treatments still involve broad immunosuppression with potentially severe adverse effects. Hence, there is a huge gap between the increasing insights into the immune mechanisms and pathogenic role of autoantibodies against cellular antigens on the one side and the currently available treatments with limited specificity on the other side. The vision of AUTO-TARGET is the development and experimental implementation of pathogenesis-based and antigen-specific treatments for autoimmune diseases of the kidney. The objectives are (1) to identify and characterize novel molecular targets on autoantibody-secreting cells, (2) to target autoreactive B and plasma cells using nanobody-based compounds, and (3) to engineer chimeric autoantibody receptor NK and T cells for the treatment of different autoimmune diseases of the kidney. AUTO-TARGET thereby revolves around a highly translational approach, combining target identification and characterization in patients with autoimmune kidney diseases with unique in vitro and in vivo systems to model disease and validate therapeutics. These translational studies pave the way for more specific, less toxic treatments and thus may implicate a huge step forward for the large and growing population of patients with kidney disease.

Tuberculosis (TB) is a global disease. With over 1.6 million deaths in 2017 alone and an estimated one quarter of the world’s population infected with Mycobacterium tuberculosis (Mtb), the etiological agent, TB is found throughout the world. Mtb is highly successful as a pathogen, in part due to its distinct and hydrophobic outer membrane (OM) and its type VII secretion systems (T7SSs). Although critical for the success of Mtb as a pathogen, the structure and mechanism of T7SSs are still poorly understood. In Mtb, five T7SSs (ESX-1 to 5) perform diverse functions such as immunomodulation, virulence, uptake of nutrients and iron. In T7SSs, four conserved membrane components, EccB/C/D/E assemble into a hexameric inner membrane complex, with a fifth transiently interacting membrane component, MycP. We have previously shown a low resolution, hexameric structure of the EccB/C/D/E membrane complex and recently two models of a dimeric subcomplex have been published. However, little is known on the structure of the entire core complex (including MycP), what is the secretion pore and how is it gated, or how secretion takes place through the OM, making this research proposal timely and necessary. The aim of this fellowship is to elucidate the underlying mechanism of secretion through the diderm cell envelope by: 1 - Elucidating the high-resolution structure of the hexameric T7SS membrane complex of Mtb. 2 - Investigate the molecular and structural mechanisms behind the OM translocation process. The results stemming from this proposal have the potential to aid and steer structure-based drug designs against Mtb. The host lab has pioneered cryo-EM of secretion systems and has state-of-the-art infrastructure and know-how that will provide the fellow with the best possible training and chances of success. With appropriate measures put in place, this project will drive forward mycobacterial research and will serve as a starting platform for identifying new possible drug targets.