Project A02: Humanized mice to study the zoonotic potential and pathophysiology of hepatotropic emerging pathogens

A number of emerging viruses have been associated with liver disease, including new hepatitis B-like viruses from bats, and other not strictly hepatotropic viruses such as EBOV, DENV and YFV. We hypothesize that the capacity of emerging viruses to replicate in liver cells impacts pathophysiology and disease outcome. We will develop and use distinct humanized and chimeric mouse models to understand zoonotic potential, hepatotropism and pathophysiology of these viruses, and establish models to study yet unknown emerging pathogens (Pathogen ‘X’).

Project leaders:

Prof. Dr. Maura Dandri, UKE
Dr. Estefanía Rodríguez, BNITM

Project A05: Pathophysiology of severe manifestations of Lassa fever

Lassa fever (LF) is recognised by the WHO as a priority disease for urgent R&D. About 20% of LF patients die in hospitals in West Africa. We hypothesise that severe Lassa fever presents either as septic shock syndrome with acute kidney injury, hyperinflammation, impaired coagulation and endothelial dysfunction or as an acute neurological condition with seizures and encephalopathy. We will conduct comprehensive clinical, biomarker, human tissue and organoid studies to elucidate these pathophysiological features with the aim of developing host-specific therapies.

Project leaders:

Dr. med. Till Omansen, UKE, BNITM
Prof. Dr. Michael Ramharter, UKE, BNITM
Prof. Dr. Stephan Günther, BNITM

Project B03: Structural cell biology of Bunyaviruses

Bunyaviruses cause regular outbreaks and therefore pose an imminent threat to global public health. Our understanding of the biology of these viruses is however limited. Although structures of the isolated bunyavirus L protein, a key player in viral genome replication and transcription processes, have been solved, knowledge on the broader context of these processes is needed to understand the involved host and viral factors and their spatiotemporal functional orchestration inside cells. By obtaining information on protein-protein interfaces we will be able to identify novel Achilles heels for the development of antiviral strategies.

Project leaders:

Dr. Maria Rosenthal, CSSB, BNITM
Prof. Dr. Kay Grünewald, CSSB, LIV, UHH

Project B04: Determinants of heterospecific phase separation in negative-strand RNA viruses

The goal of B04 is to create broad-spectrum antivirals against negative-strand RNA viruses like Ebola and Lassa and a potential disease X by inhibiting viral liquid-liquid phase separation, resulting in viral inclusion body formation, which is crucial for replication. Using a novel live-cell Click-approach for viral RNA labeling, we will identify viral and cellular proteins in functional viral condensates. We will employ neural networks and wet lab confirmation to decode the sequence “grammar” driving this recruitment. This approach will guide the development of inhibitors targeting viral condensate formation as a new class of antivirals.

Project leaders:

Prof. Dr. Jens Bosse, CSSB, MHH
Prof. Dr. Chris Meier, UHH, CSSB

Project C01: Protective early response patterns of innate cellular immune crosstalk in hemorrhagic fever virus infection

The main hypothesis is that strong activation of natural killer (NK) cells prevents viral spread and excessive tissue inflammation in viral haemorrhagic fevers. Using closely related pairs of pathogenic and apathogenic arena- and filoviruses, we will investigate how infected macrophages activate NK cells and what factors render them resistant to NK cell killing. We will use cerebral organoids to study the brain-specific macrophage response to viral infection, as rapid control of inflammation is essential in this tissue. The long-term goal is to identify targets for NK cell-based therapies to improve viral control and resolve inflammation.

Project leader:

Dr. Dr. Angelique Hölzemer, UKE, LIV

Project C04: Multidimensional analysis of protective and damaging adaptive immune responses in emerging viral infections

The ability to quickly analyze host immune response patterns to novel viral infections and mechanisms of immune evasion are key for pandemic preparedness. Thus, we focus on analyzing host immune responses to emerging viruses. We hypothesize that initial naïve adaptive immune responses, while aiding in pathogen clearance, might lead to hyperinflammation or autoimmune-like reactions. Additionally, we aim to examine the switch from innate to adaptive immunity, especially in immunocompromised and re-infected vaccinated patients to gain insights into immune dynamics.

Project leaders:

Prof. Dr. Mascha Binder, Universitätsspital Basel, UKE

Prof. Dr. Julian Schulze zur Wiesch, UKE

Project D01: Characterization of host factors as targets for the development of broadly acting therapeutics against emerging viruses

This project addresses two parts to design broad-spectrum active molecules. Highly active and selective inhibitors against the host-cell enzyme DHODH will be developed. DHODH is essential for the de-novo-biosynthesis of pyrimidine nucleosides. Moreover, nucleoside analogue triphosphates will be synthesized and evaluated against viral RNA-polymerases. Inhibitory triphosphates will be converted into their pronucleotide forms to enable membrane-permeability. The project aim is to block two essential enzymes as a new combinational intervention approach also applicable to tackle “Disease X” in the future.

Project leader:

Prof. Dr. Chris Meier, UHH

Project D02: Metagenomics in emerging viral infections – integrating non-host and host transcriptional responses

D02 seeks to advance pathogen detection through metagenomic and metatranscriptomic methods, refining next-generation sequencing approaches. It involves cataloging microbial and host-derived sequences, creating expression signatures for specific diagnostic entities, and developing host signatures for viral families. Leveraging expertise in viral genomics, the project integrates nucleotide sequence-independent methods for pathogen detection. Furthermore, it aims to predict infectious diseases by analyzing disease-associated host responses, addressing challenges posed by unknown pathogens like “Disease X”.

Project leader:

Prof. Dr. Nicole Fischer, UKE