Which paths lead to new inhibitors against human adenoviruses?

What is this research project about?

Replication cyclus Human Adenovirus (HAdV): After the receptor mediated endocytosis of the HAdV, the viral early genes are transcribed.

What is this research project about?

Human adenoviruses (HAdV) are widespread pathogens of the respiratory tract, digestive tract and urinary tract that cause highly infectious follicular epidemic keratoconjunctivitis, i.e. simultaneous inflammation of the conjunctiva and cornea of the eye, and fatal diseases in immunocompromised individuals. Alarmingly, new types have recently been reported that predominantly affect the lungs and can kill healthy people. In the absence of HAdV-specific chemotherapy, a future challenge for basic research will be to provide the background for innovative future antiviral intervention strategies.

HAdV are also commonly used as viral vectors in vaccination strategies (SARS-CoV), gene therapy and tumour therapy because of their high gene delivery efficacy and ease of manipulation. Nevertheless, there are still many gaps in basic knowledge that need to be filled by future discoveries with immediate translation into clinical applications.

What’s the current status?

To date, there is no effective chemotherapeutic drug to treat HAdV infections. Common antiviral treatments such as cidovovir and ribavirin only limit HAdV, but cannot cure severe infections or save patients. Therefore, there is an urgent need to understand the unknown collaborations between virus and host in the first steps of infection in order to develop new antiviral inhibitors that effectively prevent HAdV-mediated disease and mortality.

We are working to identify and characterise missing steps that allow HAdV to introduce genomes into a cell and convert viral chromatin to an active state to promote viral replication or amplify persistent infections with potential and often life-threatening reactivation processes, particularly in immunocompromised individuals, infants and young children.

HAdVs exploit PML-NB, not only to benefit from the transcription-activating properties of PML-NB constituents but also to counteract PML-NBs antiviral activity.

What are the project goals?

We want to know how the modulation of viral and host chromatin by the structure of the incoming virion and early viral proteins functions mechanistically to promote viral replication and efficient gene expression. Based on this scientific concept and niche, we aim to resolve open but very important questions that point to few existing examples of how viral proteins influence the establishment of chronic infections, viral latency, abortive infections, reactivation and oncogenic transformation, and how they contribute to the species barrier of human pathogenic viruses.

Our aim is to link the existing disciplines of molecular biology with basic clinical virology and medical approaches in the RESIST cluster. We believe that our scientific goals will potentially impact other research areas and provide new insights into important emerging topics in viral pathogenesis, persistence and oncogenesis. The identification of novel signalling pathways deregulated during infection and unknown determinants involved in virus-mediated chromatinisation of the genome will not only improve our understanding of epigenetic processes in the host, but also help to find new therapeutic targets to limit or prevent chronic infections, virus-mediated diseases and mortality in immunocompromised and immunocompetent patients.

How do we get there?

We are currently working to identify and characterise the missing steps that allow human pathogenic DNA viruses to introduce their genome into an infected cell, epigenetically transform it into either a transcriptionally active template for early gene expression or a persistence reservoir, and understand the initial host responses, particularly through PML nuclear bodies (PML-NBs), SUMOylation and ubiquitinylation.

Projectleader

Project title: Human Adenovirus – Viral strategies to counteract host defense

Project D5 Publications

Publications of the project D5

PML alternative splice products differentially regulate HAdV productive infection. Microbiology Spectrum. Stubbe M, Hofmann S, Masser S, Dobner T, Boutell C, Groitl P, Schreiner S.

Double-edged Role of PML Nuclear Bodies during Human Adenovirus Infection. Virus Res. 2;295:198280. Hofmann S, Stubbe M, Mai J, Schreiner S.

HAdV E2A SUMOylation prevents antiviral response promoted by host PML-NB components. Stubbe M, Mai J, Paulus C, Stubbe HC, Berscheminski J, Karimi M, Hofmann S, Weber E, Hadian K, Hay RT, Groitl P, Dobner T, Nevels M., Schreiner S. 2020. mBio. Mar 17;11(2):e00049-20.

TO (Arsenic Trioxide) effects on PML nuclear bodies reveals antiviral intervention capacity. Advanced Science. Hofmann S, Mai J, Masser S, Groitl P, Hermann A, Brack-Werner R, Sternsdorf T and Schreiner S. 2020. AApr; 7(8): 1902130.

Publications of the Project D5