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Ad3.0: Studying infection biology of the natural diversity of adenoviruses and implications for gene-based medicine

Subject Area Virology
Term from 2011 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 192749484
 
Final Report Year 2025

Final Report Abstract

More than 100 human adenovirus (HAdV) types divided into 7 species (A-G) were isolated. HAdV received increasing attention both as human and veterinary pathogen and as emerging therapeutics. As pathogen, HAdV causes a multitude of infections frequently affecting the respiratory tract- and gastrointestinal tract and the eyes with growing numbers of fatalities. As therapeutics, HAdV belongs to the currently most promising candidates in the group of advanced-therapy medicinal products, with high potential for the treatment of malignant tumors as oncolytic virus, as genetic vaccine against infectious diseases and as gene transfer vector for applications in gene-based medicine. Especially in the COVID-19 pandemic adenoviral vectors received high attention as vector vaccine against SARS-CoV2. Therefore, it is of high interest to further study these viruses including the complete natural diversity. In our previous work, we used advanced recombineering techniques to get genetic access to these viruses and to genetically engineer them for further scientific questions. This concept catapulted our laboratory into a prestigious situation because our resource allows gaining pivotal information about factors influencing tropism and pathogenesis of HAdV. Therefore, the major objective of this project was the expansion of this knowledge and establishing improved technologies to study the natural diversity of HAdV. In the first step, we determined conditions and optimized protocols for direct cloning of HAdV from infected material and for introduction of genetic modifications (insertions, deletions, mutations) into the HAdV genome. In the context of this project, we cloned and modified novel clinical isolates and performed basic characterization of these HAdV types. These steps were essential also allowing other research groups to use this valuable ressource. Information about the majority of human AdVs is scarce and therefore we investigated HAdV isolates with respect to usage of receptors for HAdV entry into the target cells. We developed single and double knock-out cell lines using the CRISPR/Cas9 technology lacking major HAdV receptors (CAR, CD46, desmoglein-2 [DSG-2], heparin sulfate proteoglycan [HSPG]) and we explored cells overexpressing respective HAdV receptors. Based on our preliminary results we also addressed the question whether there is a general role for CD46 and its soluble version (sCD46) in pathogenesis and virus infection biology. Based on our results the majority of HAdV utilize CD46 for cell entry and we have first hints that soluble CD46 plays a role during infection. However, further experiments need to be performed to confirm these results. In concert with information gained from specific aims above and previous work, we focused on translational approaches including primary cells such as hematopoietic stem cells which led to identification of novel interesting candidates for therapeutic approaches. We believe that our research combining basic and translational aspects of vector development will break new ground for generation of customized vectors in personalized medicine.

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