All Projects

Funding: DFG (VIPER GRK)

Project Details:
Motile cilia are microtubule-based, hair-like projections on the luminal membrane of epithelial cells in conducting airways. Through their continuous wave-like beating, they evacuate mucus secreted by goblet cells, thereby contributing to muco-ciliary clearance (MCC). In this function, motile cilia are actors of the first-line defense against inhaled pathogens. Dysregulated cilia will have a long-term effect on MCC and predispose for further diseases. Similarly, the diffuse endocrine system plays an essential role in respiratory tract imbalances. However, underlying pathogenetic mechanisms are not well understood, neither in various organs nor in the trachea and larynx. Therefore, the envisioned study will enhance our understanding of short- and potential long-term effects of SARS-CoV-2 infection in the upper respiratory tract and its associated endocrine and nervous system.

Cooperation Partners:

Institut für Virologie, Universität Münster,

Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, U.S.A (Klaus Schughart),

Helmholtz-Zentrum für Infektionsforschung (HZI), Braunschweig (Robert Geffers),

Medizinisch Hochschule Hannover (Peter Claus)

Funding: DFG, 482.000 EUR

Project Details:
Streptococcus suis is a frequent colonizer of the upper respiratory tract of pigs, but can also cause severe systemic diseases like meningitis and septicemia. However, pathogenesis of S. suis infection and the role of its virulence-associated factors, namely the pore-forming toxin suilysin (SLY) and the D-alanine-D-alanyl carrier ligase (DltA), is still not fully understood. So far, it is known that SLY damages different host cells by lytic pore formation and induces an inflammatory response leading to the release of cytokines, especially by monocytes/macrophages, and the recruitment of neutrophils. D-alanylation of lipoteichoic acids in the cell wall by DltA is known to increase resistance against antimicrobial peptides (AMPs) and phagocytosis of S. suis by neutrophils.
Our aim is to clarify the role of SLY and DltA in S. suis colonization of the porcine respiratory tract, systemic dissemination via the bloodstream, and invasion of the central nervous system. Thereby we will focus on their influence on innate immunity cells and the crosstalk between monocytes/macrophages and neutrophils. We hypothesize that the host compartments influence the expression of sly and dltA differentially and that vice versa SLY and DltA influence the host?s innate immune response by modulating the crosstalk between neutrophils and monocytes/macrophages contributing to the resistance of. S. suis towards immune defense mechanisms.
To investigate this, we will use complex in vitro cell culture systems that closely mimic the in vivo situation of the three main host compartments: a co-culture system of primary respiratory epithelial cells differentiated under air-liquid interface conditions and alveolar macrophages, porcine precision-cut lung slices, a reconstituted whole blood model, and the blood cerebrospinal fluid barrier model. Infection experiments will be performed with S. suis serotype 2 wild-type strain (wt), its isogenic mutants Δsly, ΔdltA, and ΔdltAΔsly as well as the respective complemented mutant strains.
We will start with the analysis of sly and dltA expression in the three compartments by quantitative real-time PCR and Western blotting, followed by the investigation of the neutrophil and the monocyte/macrophage response towards S. suis wt and sly- and dltA-deficient mutants. We will focus on the formation of neutrophil extracellular traps, reactive oxygen species production, phagocytic activity, and the release of certain cytokines and AMPs. Finally, we will investigate how secretions from monocytes/macrophages induced by S. suis infection influence neutrophils regarding their transmigration, inflammatory response, and phagocytic capacity, and vice versa.
The detailed investigation of the innate immune response towards S. suis infection in the three different compartments will help to better understand the switch of S. suis as a colonizer to an invasive pathogen, and how SLY and DltA are involved in this process.

Cooperation Partners:

Dr. Sophie Öhlmann (Institut für Bakteriologie und Mykologie, Veterinärmedizinische Fakultät, Universität Leipzig)

Funding: The International Human Frontier Science Program Organization (HFSP), 1.106.000 EUR

Project Details:
Insect cell membranes differ from mammalian membranes by deformability, lipid content and distribution. Enveloped insect-borne viruses require intimate interactions with cellular
membranes to enter cells, replicate their genomes in cells and bud from cells. Despite fundamental biophysical differences between insect and mammalian membranes, viruses can productively infect cells from both phyla. Decades of studies on insect-borne viruses have not addressed the machinery of insect membrane deformation and its exploitation by viruses. Working at the interface of insect genetics, biophysics and infection biology, our newly formed team has assembled innovative technologies to break through this barrier in the field. Through the combined expertise of the PIs, we will: 1. Employ gene editing libraries in insect cells to identify host factors steering virus - membrane interactions; 2. Image membrane deformation at high resolution; 3. Assess the impact of membrane deformation on permissiveness to insectborne viruses. These studies will provide insight into mechanisms driving insect membrane shape and revolutionize our understanding of virus adaptation across fundamentally different
species.

Cooperation Partners:

Dr. Nicholas Ariotti, Institute for Molecular Bioscience, Australia

Dr. Norbert Perrimon, Harvard Medical School, USA

Funding: DFG, 498.400 EUR

Project Details:
The equine recurrent uveitis (ERU) is the main reason for blindness in horses, and 10% of the european horses are affected. Significantly, ERU is an important available model for human autoimmune uveitis as the clinical and immune-pathological characteristics are similar. As a cause for ERU, various hypotheses are described in the literature. On the one hand, infections with Leptospira interrogans are discussed as well as other bacterial, parasitic or viral infections. Independent of the initiating cause, there are numerous indications that ERU is an immune-mediated disease. In the body after the control of the primary infection, an overreaction of the immune system occurs in response to activated immune cells. In addition to lymphocytes, these immune cells can also be neutrophil granulocytes. Among various antimicrobial functions, neutrophils have been shown to release neutrophil extracellular traps (NETs). NETs are extracellular DNA fibers with associated proteases and antimicrobial peptides which are released by activated cells. NETs mediate entrap of invading pathogens, but when massively released may contribute to detrimental autoimmune reactions of the host.
The research project presented here is intended to provide essential insights for the involvement of NETs in the pathogenesis of ERU. In the first phase of our study, our findings indicate an involvement of NETs in the pathogenesis of ERU with detrimental effects. In short, NETs correlate to disease severity, seem to damage the blood retinal cells, and induce autoantibodies against NET proteins. We hypothesize, that those autoantibodies might shield the NETs from degradation by DNases, resulting in their persistence and potentially in new disease episodes. Thus, in the current project we aim to characterize if and how the phase of disease (non-active quiescent phase versus acute inflammatory phase) influences cellular involvement and extracellular DNA release. Based on our previous data, we further hypothesize that different cell types besides neutrophils play a role in extracellular DNA release during the progression of ERU, which enables crosstalk between various immune cells. Therefore, we will study the release of ETs by other immune cells besides neutrophils and its interplay with adaptive immune cells. Finally, since the use of gentamicin in the treatment of ERU patients is well established, the aim is to determine the influence of gentamicin in varying concentrations and along with distinct stimuli on equine immune cells, focusing on ET release.
 

Funding: Niedersächsisches Ministerium für Wissenschaft und Kultur (MWK), 324.000 EUR

Project Details:
The aim of this subproject is the further development and optimization of a 3D lung epithelial cell culture model
for the investigation of viral and bacterial infections and the effect of immunomodulatory
immunomodulatory substances on the course of infection and cell biochemical processes. An increased
complexity of the model system using physiological or pathophysiological oxygen
conditions and microfluidic systems enables the in vitro system to be approximated to the in vivo situation and
to the in vivo situation and will help to reduce the number of test animals in the long term. The
complexity of the infection model is reduced by physiologically relevant oxygen conditions (defined
tissue-specific hypoxic conditions) and by 3D co-cultivation of human or animal pulmonary
or animal pulmonary epithelial cells and neutrophil granulocytes. In addition
the use of primary cells and induced pluripotent stem cells should provide long-term optimization.

Funding: Bundesministerium für Bildung und Forschung, 625.000 EUR

Project Details:
As long as animal experiments cannot be completely replaced, the question will arise on which animals research should take place. In this project, an interdisciplinary working group wants to investigate the ELSA-relevant question, according to which criteria the selection of laboratory animal models takes place or should take place. The aim of the enterprise is to determine the manifold reasons for the choice of certain laboratory animals; the process is interdisciplinary in the full sense of the word and put the different rationalities into a well-founded correlation. The question condenses several open and important issues concerning the treatment of animals. The answer is to be examined in each of the disciplines involved, between them and finally in their association, whether it is possible to establish a coherent catalog of criteria that also creates clarity for the practice of animal experimentation, both for everyday research and at the interface to legislation and enforcement. This is important against the background of rapidly changing social value judgements about animals, which also lead to permanent tensions here. In this project we want to investigate the ELSA-relevant question of the criteria for the selection of laboratory animal models. We follow an interdisciplinary approach, which is represented by the following cooperation partners: Its members are: Prof. Dr. Peter Kunzmann (ethics), Prof. Dr. Bernhard Hiebl (laboratory animal science), Prof. Dr. Maren von Köckritz-Blickwede (infection research) (all TiHo- Hannover) and the legal scientist Prof. Dr. Dr. Tade Spranger (University of Bonn).

Cooperation Partners:

Tade Spranger, Rechts- und Staatswissenschaftliche Fakultät, Bonn

Funding: MWK über Universität Göttingen, 439.500 EUR

Project Details:
Das Projekt befasst sich mit der Auswirkung einer SARS-CoV-2-Infektion auf die Integrität der Epithelien im Respirationstrakt, mit besonderem Fokus auf die Spätfolgen der Infektion und die Regenerationsfähigkeit. Hierzu wird ein Langzeitversuch im Hamstermodell durchgeführt, in dessen Rahmen Daten für zwei Kernarbeitspakete generiert werden. Im ersten Arbeitspaket werden Auswirkungen auf das ziliierte Epithel in den luftleitenden Wegen untersucht, während das zweite Arbeitspaket sich mit der Schädigung und Regeneration des Alveolarepithels und der daraus resultierenden Folgen für die Lungenfunktion, den Sauerstoffaustausch und die Belastungstoleranz beschäftigt. Zur Auswertung kommt ein breites Spektrum von Analysemethoden zum Einsatz, inklusive funktioneller, pathologischer, virologischer und molekularbiologischer Methoden. Der holistische Ansatz wird unser Verständnis der Pathogenese der Spätfolgen einer COVID-19-Erkrankung maßgeblich erweitern und stellt eine wichtige Voraussetzung für die Entwicklung von Therapieansätzen dar.

Cooperation Partners:

Universität Göttingen

Funding: MWK über Universität Göttingen, 266.300 EUR

Project Details:
Das Mikrobiom der Lunge erfüllt, obwohl signifikant kleiner als das des Darms, eine bedeutende Funktion bei der Regulation der lokalen Immunantwort. Aktuelle Studien zeigten außerdem das SARS-CoV-2 Infektionen bei Betroffenen zu einer Veränderung in der Zusammensetzung des Lungenmikrobioms führen. Im Rahmen des Projektes soll untersucht werden, ob eine durch eine gezielte Manipulation des Lungenmikrobioms ausgelöste Verschiebung der Typ-1-Interferon-Reaktivität in der Lunge die systemische Anfälligkeit für eine SARS-CoV-2-Infektion beeinflusst. Während in der ersten Phase eine genauere Untersuchung der Rolle des Lungenmikrobioms bei der Regulation der homöostatischen Immunantwort erfolgt, wird in der zweiten Phase des Projektes darauf aufbauend die Rolle der Lungenmikrobiota bei der Regulierung der lokalen und systemischen Immunantwort im Rahmen einer SARS-CoV-2-Infektion untersucht. Wenn die in diesen Experimenten gewonnen Daten darauf hindeuten, dass Veränderungen im Lungenmikrobiom einen Einfluss auf den Verlauf der Infektion haben, soll in einem letzten Experiment der Einsatz von Probiotika als pharmakologische Behandlung von SARS-CoV-2-Infektion erprobt werden.

Cooperation Partners:

Universität Göttingen

Funding: Deutsche Forschungsgesellschaft (DFG), 110.700 EUR

Project Details:
Tetraspanins are evolutionary conserved integral membrane proteins of 200-350 amino acid lengths. Through their large extracellular loop they mediate protein - protein and protein - lipid interactions in cellular membranes thereby shaping membrane microdomains called ?tetraspanin webs?. In humans and mice 33 tetraspanins are described and mosquito species express at least 15 tetraspanin orthologs. In mammalian cells, tetraspanins are host co-factors for several viruses including papillomaviruses, influenza virus, hepatitis C virus, HIV-1 and coronaviruses (Gerold et al., 2015; Bruening et al. 2018; Banse et al., 2018; Alberione et al. 2020; Palor et al., 2020). For hepatitis C virus, colleagues and we showed that the tetraspanin CD81 is a host range determining factor (Vogt et al. 2013; Scull et al., 2015; von Schaewen et al., 2016).
The proposed project aims at characterizing in detail, which of the 33 human tetraspanins in addition to CD81 are host factors for alphaviruses and whether tetraspanins from reservoir species, dead end host species and transmitting mosquito vectors serve as host factors of alphaviruses. Thereby the work will contribute to the understanding of the molecular composition and function of alphavirus replication complexes and determine the role of tetraspanins in species range, transmission and consequently emergence of alphaviruses.

Funding: DFG (VIPER GRK)

Project Details:
The exact pathomechanisms that lead to the development of long-term consequences after an acute SARS-CoV-2 infection - also known as long-COVID - are still largely unknown. Since only limited sample material from surviving patients with long-COVID is available, the use of a suitable animal model is essential to investigate the underlying mechanisms. In this project, the Syrian golden hamster was established as a model animal to study the pathogenesis of long-COVID. Initially, a short-term study was conducted to investigate the alveolar regeneration mechanisms, in which a morphological homology to the processes in the human lung after s SARS-CoV-2 infection was found. In a further long-term study over four months, morphological, molecular biological and lung function analyses were combined. The course of the disease in the animals showed three phases: acute, subacute and chronic. While the acute phase was characterized by severe breathing restrictions, these only occurred after exercise in the later phases and disappeared entirely after about 6 weeks. Histologically, there was persistent fibrosis and alveolar bronchiolization with club cell proliferation. Transcriptome analysis showed, among other things, an upregulation of pro-fibrotic genes. In the future, long-term consequences in the brain will be investigated primarily by transcriptome analysis, and the role of the pulmonary neuroendocrine system, which is connected to the central nervous system via afferent nerve fibers, will be examined in more detail.

Results:

Paper 1: https://www.nature.com/articles/s41467-023-39049-5 ; Nature Communications, 2023

 

Paper 2: https://www.researchsquare.com/article/rs-4681343/v1 ; (preprint Version), accepted at Nature Communications, 2025