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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: 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

Project Details:
The persistence of Actinobacillus pleuropneumoniae (App) on the tonsils facilitates the spread of the pathogen in pig populations. Microbiological-cultural detection of the pathogen from tonsils has proven to be difficult because the diverse commensal colonization by other bacteria (e.g., Streptococcus suis) often overgrows App during culturing. The use of selective media leads to higher sensitivity of bacteriological diagnostics, but nevertheless, the success rate compared to molecular biological tests (PCR) is not satisfactory.
In most cases, acute outbreaks of porcine pleuropneumonia occur in persistently infected pigs under the influence of trigger factors. In vitro, the influence of stress hormones, such as cortisol and catecholamines on the growth behavior of the pathogen will be investigated. Possibly, catecholamines and cortisol can be used under in vitro conditions to improve the growth behavior of A. pleuropneumoniae.

Funding: Boehringer Ingelheim Vetmedica GmbH, 16.666 EUR

Project Details:
Zeitgleiche Isolierung und Charakterisierung von S. suis und PRRSV aus Organsystemen sezierter Schweine. Charakterisierung der Effizienz der Immunausweichmechanismen von S. suis Isolaten.

Funding: Boehringer Ingelheim Vetmedica GmbH, 16.666 EUR

Project Details:
Koinfektionen mit Streptococcus (S.) suis und PRRSV verursachen häufig schwerwiegende Erkrankungen auf Schweinebetrieben. Synergistische Effekte beider Erreger wurden auch unter Laborbedingungen bestätigt.
Ziel dieser Studie ist, von erkrankten und zur Diagnostik überwiesenen Tieren Isolate beider Erreger zu gewinnen und unter in-vitro Bedingungen mit unterschiedlichen Testverfahren entsprechend ihres Wachstumsverhaltens und ihrer Interaktion mit Immunzellen des angeborenen Immunsystems einzeln und in Koinfektion zu charakterisieren.

Cooperation Partners:

Institut für Virologie, Tiermedizinisce Fakultät, Universität Leipzig

Funding: EU-ERASMUS, 162.864 EUR

Project Details:
VETvip zielt darauf ab, die naturwissenschaftlichen Grundlagen stärker mit der tiermedizinischen Praxis zu verknüpfen. Ziel ist es, den Lernerfolg der Studierenden zu steigern. Gemeinsam mit der TiHo beteiligen sich die veterinärmedizinische Fakultät der Szent Istvan Universität in Budapest, die veterinärmedizinische Fakultät der naturwissenschaftlichen Universität in Lublin und die Instruct AG aus München an diesem Projekt.

Cooperation Partners:

Universität Lublin

Universität Budapest

Instruct AG