Overview of research projects

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

Project Details:
Cooperation strengthens cohesion between animals and is thus a decisive factor for social systems. The present project aims to investigate how individualised relationships - reflected in different types, and amounts, of socio-positive interactions between dyads - shape the social system in a bat model, Carollia perspicillata. A first study will disclose the effects of the interacting individuals, and sex, on cooperative behaviours among bats roosting in stable groups. A second study serves to pinpoint the effect of familiarity on cooperation, using allogrooming and food begging/sharing as paradigms in a series of behavioural experiments. Differences in type, frequency, and duration of interactions, and in the concomitant vocal communication, are expected for experiments with unfamiliar individuals versus those with bats from a given roosting group. The results will contribute to a deeper understanding of how cooperation between individuals may have driven the evolution of bat sociality.

Cooperation Partners:

Prof. Dr. Gerald Kerth,, Zoology and Nature conservation, Zoologisches Institut und Museum, Universität Greifswald

Project Details:
Neurons in the dorsal nucleus of the lateral lemniscus (DNLL) are relevant for binaural processing especially during reverberations. Their basic biophysical and synaptic properties have been documented, but are not understood on the cellular and molecular level. It remains so far unclear what voltage gated ion channels (VGIC) underly their functional specifications and how synaptic inputs are modulated. One specific question that will be answered his how different VGIC (potassium and sodium channels) interact to allow these neurons to generate high firing frequencies at high temporal precision. This biophysical phenotype indicates that these features are differently solved compared to other auditory brainstem neurons with similar tasks. Thus, this project aims to understand the moleculare organisaiton of the postsynaptic integration and spike generation mechanism. Since, the GABAergic DNLL neurons are reziprocally connected substantial GABA is liberated onto each neuron. GABA not only leads to fast inhibitory singalling but also is well-documented to generally be an important neuromodulator in the auditory brainstem. Therefore, the action of GABA mediated neuromodulation will be investigated by characterizing its effect on synaptic inputs and VGIC.

Results:

Javadova A, Felmy F.: GABAB receptor-mediated modulation in the developing dorsal nucleus of the lateral lemniscus. European Journal of Neuroscience (2024) Jan 5. doi: 10.1111/ejn.16246.

Funding: DFG, 350.510 EUR

Project Details:
In mammals, brain and neuron size enlarges with increasing head size. Inevitably, an increase in neuron size results in an increased membrane capacitance. To achieve size-independent synaptic integration and, thus, the function, neuronal properties like input resistance, dendritic morphology, synaptic conductance as well as the number and location of ion channels and synapses must scale proportionally. A prerequisite to investigate the cellular mechanisms of such a scaling is an evolutionary conserved neuronal population that fulfills the same circuit function independent of head and brain size. The neurons of the medial nucleus of the trapezoid body (MNTB) fulfill these criteria and are involved in binaural processing and spectro-temporal integration in the ascending auditory pathway. Quantification of the biophysical and morphological cellular parameters of MNTB neurons and their synaptic input size as well as channel and synapse location in differently sized mammalian species, i.e. Etruscan shrew, gerbil and rat, allows us to grasp the consequences of brain size-dependent neuron scaling. Our electrophysiological and immunofluorescence findings will culminate in a computational model to understand the functional significances of individual neuronal elements. Moreover, we can utilize this comparative approach to investigate the functional role of MNTB dendrites, which remains largely unknown. Specifically, by quantitatively determining the influence of dendritic synaptic inputs on synaptic latency and the success of action potential generation, we can capture their potential role in the generation of high frequency outputs.

Project Details:
Etruscan shrews need to constantly hunt to meet their energy requirements; because of their small body size, their relative energy consumption is very large. To efficiently hunt in close range, these animals rely especially on tactile sensory cues. However, for long-range detection of prey these animals likely use their well-developed hearing. Due to their small body and head size, these animals are expected to hear in frqeuncy range above 5 kHz and therefore are an ideal model system to investigate high frequency hearing and adaptations to miniaturization of mammalian neuronal circuits. We attempt to describe their auditory brainstem strucutes by applying structural and functional markers. After the initial anatomical characterization we will use electrophysiological techniques to comparatively study the properties of adutiory brainstem neurons. Thereby we will focus on biophysical and synaptic size adaptations within conserved neuronal circuits.

Project Details:
A vocal repertoire contains a species-specific list of vocalizations, which are produced by the animals. These lists build the methodological and theoretical basis for a number of research questions of different disciplines. Nevertheless, there is no consensus how to establish a vocal repertoire or how to define call types. In the majority of studies, call types were established by visual classification, using spectrograms, which was supported by statistical analysis based on the measured acoustic features of a vocalization. In recent publications, more objective mathematically approaches such as supervised or unsupervised clustering algorithm were established. However, also these algorithm often require a pre-screening of the observer either because a number of expected clusters has to be determined or by the fact that the clustering result has to be proofed for their biological plausibility. Both methods can lead to an overestimation of call types especially in species with very variable vocalizations or graded call types. Thus, an acoustic variation alone is not sufficient to reflect a behavioural relevance. This also requires a context-specificity and the ability of the brain to perceive and process the acoustic variation. In this project, we aim to establish the vocal repertoires by combining the mathematical classification of the vocalizations with the behavioural contexts in which the calls were produced as well as the physical hearing abilities (e.g., hearing range, time- and frequency resolution) of the given species. We use this approach for two small-bodied mammalian species: the Mongolian gerbil, an important animal model for human hearing, and the Etruscan shrew, suggested to be a promising model for hearing in basal mammals due to its small eardrum, basal ossicles, and simple and thin cortex.

Results:

Langehennig-Peristenidou A, Felmy F, Scheumann M (2024). Graded calls of the smallest terrestrial mammal, the Etruscan shrew, living in a closed habitat. iScience, 27(12), 111297. DOI:10.1016/j.isci.2024.111297

 

Silberstein Y, Büntge J, Felmy F, Scheumann M (2024). Context or arousal? Function of drumming in Mongolian gerbils (Meriones unguiculatus). Frontiers in Zoology, 21(1), 22. DOI:10.1186/s12983-024-00542-2

 

Silberstein Y, Felmy F, Scheumann M (2023). Encoding of arousal and physical characteristics in audible and ultrasonic vocalizations of Mongolian gerbil pups testing common rules for mammals. Animals (Basel), 13(16), 2553. DOI:10.3390/ani13162553

Cooperation Partners:

Prof. Dr. A. Kral, VIANNA, Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde

Dr. Wiebke Konerding, VIANNA, Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde

Funding: Alexander von Humboldt-Stiftung, 51.831 EUR

Project Details:
Antimicrobial resistance (AMR) is a global challenge worldwide, and generally results from consumption of antimicrobials. Antimicrobial use (AMU) in animal production is part of these processes and has been recognized as a source of global burden of AMR. Surveillance of veterinary AMU and AMR and its reduction is one of the strategic objectives of many regional and global initiatives on antimicrobial resistance crisis. Since, the resistance to critically important antimicrobials like colistin, particularly due to mobile colistin resistance gene (mcr-1), has already been reported in Pakistan from commercial broilers, wild birds and human. Therefore, data on antimicrobial usage and its association with resistance should be prioritized in food animals. Although Pakistan?s National Action Plan on AMR urged to monitor and reduce antimicrobials use and resistance in animals, little effort has been done to curb AMR in food animals. The objective of this project is to quantify AMU in commercial broiler farms in Pakistan and its association with the emergence of AMR in commensal E. coli isolates from broilers. The proposed study will fill the important knowledge gap on the AMU of critical importance antimicrobials in broilers farming, phenotypic antibiotic resistance and genomic characteristics of multidrug resistant E. coli using next generation sequencing approach. The association between AMU and AMR will be determined using statistical approaches. Our work will be an important contribution toward understanding the interplay between AMU and AMR at farms-level in Pakistan and other low- and middle-income countries with comparable farming practices.
This project comes under One-Health remit on antimicrobial resistance and aligns perfectly with the work at University of Veterinary Medicine, Foundation, Hannover which has been also designated as the WHO Collaborating Centre for Research and Training for Health at the Human-Animal-Environment Interface.

Results:

Umair M, Mohsin M, Sönksen UW, Walsh TR, Kreienbrock L, Laxminarayan R. Meas-uring Antimicrobial Use Needs Global Harmonization. Glob Chall. 2021 Jun 10;5(10):2100017. doi: 10.1002/gch2.202100017.

 

Mohsin M, Farooq U, Hartmann M, Brogden S, Kreienbrock L, Stoffregen J. Case Study: Using a Shared International Database to Document Veterinary Consumption of Antibiotics in Pakistan. Antibiotics (Basel). 2023 Feb 15;12(2):394. doi: 10.3390/antibiotics12020394.

Cooperation Partners:

Institute of Microbiology, University of Agriculture Faisalabad, Pakistan

Funding: DFG, 255.550 EUR

Project Details:
Bovine Viral Diarrhea/ Mucosal Disease (BVD/ MD) is an economically important notifiable disease of cattle. The causative agent, BVD virus (BVDV), is a plus strand RNA virus of the family Flaviviridae, genus Pestivirus. BVDV is known to enter oronasally and through the respiratory tract, from where it spreads to various organs and tissues. The initial stage of infection is poorly understood. In the context of preliminary work it was shown that non-differentiated polarized respiratory epithelial cells are highly susceptible to apical and basolateral infection with BVDV, but virus release occurs only via the apical side of the cells. Thus, it remains unknown how pestiviruses cross the barrier of the airway epithelium. However, it is well established that BVDV and other pestiviruses have a strong tropism for immune cells. Therefore, an important goal of this project is to explore the pathway by which BVDV crosses the barrier of the respiratory epithelium and spreads from there to immune cells.
In the first part of the project, the infection of airway epithelial cells (tracheal/bronchial epithelial cells) will be investigated. Two cell culture systems established at the Institute of Virology are available for the analysis of end-differentiated cells: Air-liquid-interface (ALI) cultures and precision lung slices (PCLS). Subsequently, cells that have not yet completed differentiation or cells that are in the regeneration phase after epithelial injury will be examined. Finally, we will analyze whether BVDV can overcome the epithelial barrier in a paracellular manner by exploiting leaky junctions between cells. To find out whether the different infection characteristics in the different culture systems and under the various infection conditions depending on the degree of differentiation can be correlated or explained with the presence of the cellular receptor, the expression of the receptor for BVDV, CD46, will be analyzed. For the detection of CD46 a monoclonal antibody is available, which was produced at the Institute of Virology. Another focus will be studies on the infection of macrophages. Co-cultures of macrophages and airway epithelial cells will be established to find out whether macrophage infection can be used to overcome the epithelial barrier.
Other interesting perspectives for future projects include the role of cellular innate immunity for respiratory epithelial infection with BVDV, and viral-viral or viral-bacterial co-infections.

Funding: MWK über Universität Göttingen, 29.423 EUR

Project Details:
Schwere COVID-19-Krankheitsfälle sind durch das Auftreten einer schweren Lungenentzündung charakterisiert, die häufig einen Krankenhausaufenthalt erfordern. Bis zu einem Drittel der hospitalisierten Patienten entwickeln kritische Komplikationen, wie einen diffusen Alveolarschaden, welcher zum akuten Atemnotsyndroms (ARDS) führt. Ein detailliertes Verständnis der komplexen Pathogenese und der daraus resultierenden Krankheitskomplikationen ist dringend erforderlich, um wirksame Behandlungsstrategien für die SARS-CoV-2-Infektion zu entwickeln. Mehrere erfolgreiche Präventionsstrategien wie Impfstoffe wurden entwickelt und für ihre Anwendung beim Menschen zugelassen. Wir sind jedoch noch weit von einer Eindämmung der Krankheit entfernt und könnten mit dem vermehrten Auftreten von Virusvarianten vor zusätzlichen Herausforderungen stehen. Zwar ist bereits viel über die Pathogenese und Behandlung der akuten COVID-19 Erkrankung bekannt, jedoch wissen wir immer noch sehr wenig über die potentiellen Langzeitfolgen. Es wird immer deutlicher, dass eine protrahierte Genesung ein häufiges Merkmal COVID-19 ist, ein Phänomen, das allgemein als "Long-COVID" oder Post-COVID-Syndrom bezeichnet wird. 30-60% der Personen leiden nach der Genesung von einer akuten Virusinfektion an anhaltenden Symptomen wie Müdigkeit, Kurzatmigkeit und verringerter Belastbarkeit. Dieses Projekt soll dazu beitragen, die Mechanismen von "Long-COVID" besser zu verstehen und daraus neue Behandlungsstrategien abzuleiten.