Research

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, 250.000 EUR

Project Details:
It is well known that a number of viral pathogens can be detected in saliva of infected humans and animals. However, for most of these viruses the source of their presence in saliva and in the oral cavity remains unknown. While it has been reported that human salivary glands can be infected by SARS-CoV-2 and some other viruses, the role of salivary gland tissues in infection of pigs with respiratory and most enteric viruses has not been addressed so far. To characterize infection of porcine salivary glands by both respiratory viruses (influenza A virus, porcine respiratory coronavirus) and enteric viruses (transmissible gastroenteritis virus, porcine rotavirus A), differentiated salivary gland epithelial cells and organoid cultures from pigs were established by the group of the PI. In addition to porcine influenza viruses, human and avian influenza viruses will be used to investigate a possible role of porcine salivary glands in interspecies transmission and evolution of influenza virus.

Funding: DFG, 250.000 EUR

Project Details:
The bovine epithelia-choreal placenta protects the fetus from infections with numerous pathogens. However, some viruses, such as bovine viral diarrhea virus (BVDV) or bluetongue virus, are able to cross the placenta barrier during pregnancy. In the case of BVDV, diaplacental infection with non-cytopathogenic (ncp) viruses between the 40th and 125th day of gestation is a mandatory prerequisite for the establishment of persistent infections and is therefore of outstanding epidemiological importance. In contrast, infection of pregnant animals with cytopathogenic (cp) BVDV does not lead to the birth of persistently infected offspring.
An important aspect of the placenta's barrier function against pathogens is innate immunity. First, we want to investigate the innate immune response of polarized bovine placenta cells to dsRNA applied to either the basolateral or apical compartment. Moreover, we will examine the efficiency of viral replication and release of BVDV and other bovine viruses, and characterize the innate immune response after basolateral and apical infection.

Funding: EU Commission, 1.100.900 EUR

Project Details:
Work programme 2025-2027 of the EU Reference Laboratory for Classical Swine Fever

Cooperation Partners:

Dr. Christoph Staubach (FLI Riems)

Funding: IDT Biologika und von der Coalition for Epidemic Preparedness Innovations (CEPI), 484.000 EUR

Project Details:
We will study the immunogenicity and efficacy of our vaccine candidate, MVA-MERS-S, when used in different single vaccination and vaccination-booster setting in the lethal k18-hDPP4-mouse model after MERS-CoV-challenge infection. Different vaccination schedules also include different time points of challenge infection. We will characterize the activation of MERS-CoV-specific antibodies and T cells. The protective efficacy will be analyzed by morbidity, mortality and viral load in the lung and the brain a target organs. Moreover, a histopathological examination of the upper and lower respiratory tract of the animals upon challenged with MERS-CoV will show any evidence of ADE and ERD, respectively. Another study will evaluate the impact of passively transfered sera from MVA-MERS-S vaccinated mice for the outcome of protection after challenge infection.

Funding: Deutsche Forschungsgemeinschaft (DFG) , 404.650 EUR

Project Details:
The genus Pestivirus belongs to the virus family Flaviviridae and comprises RNA viruses of great relevance, like Bovine viral diarrhea virus (BVDV) and Classical swine fever virus (CSFV), which are causative pathogens of notifiable diseases. Since decades, it was commonly accepted that pestivirus infections are restricted to cloven hooved (ungulate) hosts. In the past years, several atypical pestiviruses have been discovered in non-ungulate hosts. These newly discovered pestiviruses show the typical genome organization, but are genetically highly distinct. Obviously, these novel viruses represent a new group within the pestiviruses with so far uncharacterized biological properties. In addition, such a novel pestivirus was also discovered in pigs and designated "atypical porcine pestivirus" (APPV). APPV causes a neurological disease in newborn piglets (congenital tremor) and involvement in other diseases (e.g. infertility, abortion, neonatal malformations) appears likely.
Within this research project, it was possible to adapt APPV to cell culture conditions and to propagate it. The availability of a virus isolate provided the basis for further studies to characterize the biological properties of the pathogen. Our work demonstrated that there are obviously significant differences in the cell entry of APPV and CSFV. It has been believed for long time that the complement-regulating protein CD46 is the key for pestiviruses to penetrate the host cell, but our work showed that some pestiviruses - including CSFV - use a CD46-independent mechanism for cell entry. Which cellular surface structures are used instead for cell entry is still unclear and will be the subject of further research.
The aim of the study is to provide insights into the complex, probably multi-step process of cell entry. Within this project is the aim to identify the molecular determinants of cell entry of pestiviruses and to characterize them in more detail. Several host cell factors have already been identified which apparently interact with the viral envelope proteins during early phases of viral replication and can influence virus replication. First, it has to be elucidated whether these factors directly interact with the virus particles or whether these are indirect effects, e.g. caused by binding to other cellular proteins or by an altered cell metabolism. Knowledge of the key factors for the entry of porcine pestiviruses into the host cell can make a valuable contribution to understanding the biology of the new and widespread pathogen in the pig population, APPV, as well as the properties of the long-known animal disease pathogen CSFV.

Results:

https://www.tandfonline.com/doi/full/10.1080/22221751.2024.2327385

Funding: Grimminger-Stiftung, 20.000 EUR

Project Details:
The hepatitis E virus (HEV) is mainly transmitted to humans through meat and meat products from infected animals. The transmission route via the environment through contaminated soil, water and/or (arable) plants has long been discussed. Possible vectors include manure or waste water. Many studies show that a considerable proportion of meat and sausage products as well as many wastewater and even surface water samples can be tested positive for HEV RNA. All these studies are based on RT-PCR testing, i.e. the detection of the HEV genome. In order to carry out a better risk assessment, for example when consuming food, and to be able to identify the spread of the virus and chains of infection more precisely, it is necessary to determine the intactness and thus the infectivity of the virus in such samples. In this project, meat and sausage samples as well as environmental samples in the form of manure and wastewater will be analyzed for the presence of HEV RNA as well as for the infectivity of the virus. For this purpose, a stable and efficient cell culture system has been established in recent years, which has already been successfully used to isolate HEV capable of replication from wild and domestic pig organ samples.

Funding: VolkswagenStiftung, 700.000 EUR

Project Details:
Avian influenza in humans is associated with pneumonia, inflammation and high case fatality rates. We identified CYP19A1 as a key gene involved in sex-specific lung inflammation in SARS-CoV-2 infected hamsters and humans. CYP19A encodes for the aromatase enzyme that converts testosterone-to-estradiol leading to the activation of various estrogen-regulated pathways associated with lung inflammation. Treatment of SARS-CoV-2 infected hamsters with letrozole, a clinically approved CYP19A1 aromatase inhibitor, recovered impaired lung function and overall lung health in males. We further found that also avian H7N9 influenza virus infection mediates massive upregulation of CYP19A1 in the lung of infected animals. Thus, we hypothesize that estrogen-regulated activation of inflammatory pathways in the lung play a crucial role in severe viral disease outcome. Therefore, in this proposal, we will systemically evaluate the impact of compounds that inhibit the synthesis of estrogens (using aromatase inhibitors) or interfere with estrogen-regulated down-stream pathways (using estrogen antagonists, SERMs, SERDs) against avian influenza in the hamster model. Obtained data will provide new insights into estrogen-mediated inflammatory pathways upon infection with respiratory viruses. Moreover, identification of common pathways might result in overarching drug targets to treat inflammatory lung diseases in general.

Cooperation Partners:

Evotec

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

Funding: MWK, 439.545 EUR

Project Details:
Flex-Fund project in the COVID-19 research network Lower Saxony:
Mechanisms of short- and long-term effects of SARS-CoV-2 infection on the integrity of respiratory tract epithelia

Results:

https://www.umg.eu/forschung/corona/cofoni/