05 / 2024
From left to right: Sandra Schmitt (Sparkasse Langen-Seligenstadt), Dr Yen-Ju Lin, Hagen Wenzel, Samuel Theuerkauf, Professor Klaus Cichutek, Dr Moritz Schüssler, Uwe Linder, Professor Stefan Vieths, Stefan Löbig.
Source: Paul-Ehrlich-Institut
This year marks the 13th awarding of the Langen Junior Science Award by the Paul-Ehrlich-Institut and the Association for the Promotion of the Langen Science Award. The award is endowed with €2,000. Samuel Theuerkauf (30) received first prize for his research on improving gene transfer using two markers. The second prize went to Dr Yen-Ju Lin (35) for her research on the influence of artificially generated fusion proteins on the immune system. The third prize went to Dr Moritz Schüssler (33) for his research on the influence of the restriction factor SAMHD1 on HIV-1 infections. The Junior Science Awards recognise high-calibre research leading to first author publications in recognised journals.
The three prizewinners received their certificates and congratulations on 15 April, 2024, from the Chairman of the Association for the Promotion of the Langen Science Award, Professor Klaus Cichutek, as well as from Professor Stefan Vieths, Acting President of the Paul-Ehrlich-Institut, Hagen Wenzel, member of the Sparkasse Langen-Seligenstadt Management Board, and Uwe Linder, Managing Director of Stadtwerke Langen GmbH (Langen Utility Company). First City Councillor Stefan Löbig conveyed the city's congratulations: "It is a pleasure for us to be able to support young and talented scientists every year with the Junior Science Award. The city of Langen is once again demonstrating its commitment to research and teaching. We would like to express our thanks to the Sparkasse Langen-Seligenstadt for funding this important prize again this year."
High-calibre research in all areas relevant to the medicinal products in the Paul-Ehrlich-Institut's area of responsibility is an integral part of the activities of the Federal Institute for Vaccines and Biomedicines. "The fact that the prizes have been awarded in research areas so varied as gene transfer, HIV research, and allergy immunotherapy shows how diverse our research is in connection with our regulatory tasks,"
stated Institute President Vieths.
First prize went to Samuel Theuerkauf for his first author publication titled "AAV vectors displaying bispecific DARPins enable dual-control targeted gene delivery". The aim of his research is to optimise gene transfer precisely into therapy-relevant cells of a specific disease. It is already possible to modify non-pathogenic viruses – acting as gene shuttles – to target certain cells such as immune T cells, but the vectors only recognise the targeted cells on the basis of one marker. Many therapy-relevant cells in the human organism are only clearly defined by the combination of several markers. In the case of chronically HIV-infected cells, it is the combination of the markers CD4 and CD32a. The research project involved the first ever modification of adeno-associated viral vectors (AAVs) to carry two different high-affinity binders (DARPins; designed ankyrin repeat proteins), one specific for CD4 and the other for CD32a. These bispecific AAVs transduced CD4/CD32a double-positive cells with much higher efficiency than single-positive cells and even reached the double-positive cells when they were present in minimal amounts in cell mixtures or human blood. The clear preference for double-positive cells was also confirmed in vivo in a mouse model with a small number of double-positive cells in the bone marrow of the animals. After systemic application of the vector particles, more than half of these cells, acting as a model for the HIV reservoir, were successfully transduced, i.e. the desired genes were transferred. Cell entry studies showed that bispecific AAVs enter cells more efficiently than monospecific ones. In addition, when the vectors were equipped with a CRISPR/Cas cassette targeted to the HIV genome, they prevented HIV replication in T cell cultures.
This research is the first proof of concept for high-precision and efficient gene transfer through tandem-binding domains on AAVs. This presents a new option for receptor-controlled vectors to improve the specificity and safety of in vivo gene therapy.
Dr Yen-Ju Lin received the second prize for her first author publication titled "A flagellin-conjugate protein induces dual NLRC4- and NLRP3-inflammasome activation which modulates inflammatory cytokine secretion from macrophages". In her research, Lin investigated how therapeutics against birch pollen allergies can affect the immune system. The recombinant fusion protein rFlaA:Betv1 consists of two genetically composed components: flagellin A, which is needed by bacteria for their locomotion system and is an activation signal for immune cells, and Bet v 1, an allergen responsible for birch pollen allergies. In its preliminary work, the research group had already shown that the administration of rFlaA:Betv1 can stop the development of birch pollen allergies in the mouse model. Studies had also shown that certain types of immune cells – macrophages – are partly responsible for the reduced allergic reaction by releasing anti-inflammatory messenger substances (cytokines).
Lin and the research group have now further investigated the mechanisms underlying the activation of macrophages by the fusion protein. By combining different mutants of the fusion protein, using inhibitors that block immunological processes, and using cell lines lacking certain parts of the immune system, they found that activation of macrophages by the fusion protein was mediated via two receptors of the innate immune system, namely NLRC4 and NLRP3. They are known to trigger the formation of an inflammasome, a multiprotein complex of the immune system, upon activation, which in turn mediates the release of cytokines and inflammatory responses.
The research is a contribution to a better understanding of how therapeutics that combine antigen and adjuvant in a single molecule activate the immune system, so that they can be used safely and effectively in the future not only for allergy immunotherapy, but also for the treatment of other diseases.
The third prizewinner is Dr Moritz Schüssler. He was recognised for the first author publication titled "Gene editing of SAMHD1 in macrophage-like cells reveals complex relationships between SAMHD1 phospho-regulation, HIV-1 restriction, and cellular dNTP levels".
Schüssler and his colleagues researched the role of the protein SAMHD1 (sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1) in HIV-1 infections. SAMHD1 is a restriction factor for HIV-1. Its antiviral activity is regulated by phosphorylation at the T592 position. A new methodology involved the introduction of specific mutations into the genome of these cells, which allowed the connection between phospho-regulation, enzymatic activity, and antiviral function to be genetically decoded. The use of BLaER1 cells as a new cell model for HIV-1 infections made it possible to investigate these mutations in a physiological context. The results showed that the antiviral activity of SAMHD1 and its enzymatic function are not always directly related. These findings highlight the complexity of the relationship between SAMHD1, HIV-1 infections, and cellular functions. The study could open up new avenues for the development of therapies that target SAMHD1 without disrupting other cellular processes and contribute to the study of innate antiviral immunity.
Updated: 15.04.2024
