Modulation of adenovirus replication by antiviral and immunosuppressive agents

Abstract

Human adenoviruses (AdVs) are widespread pathogens transmitted by aerogenic or direct contact. In otherwise healthy persons, AdVs infections mostly cause self-limiting respiratory disease, diarrhea and ocular infections. At the same time, AdVs can be life-threatening for immunocompromised individuals. Children in particular are vulnerable when receiving immunosuppressive or cytostatic drugs in the context of hematopoietic stem cell transplantation. Despite the clear medical need, there is no approved anti-AdV therapy. The aim of this master thesis is to investigate whether and how antiviral, immunosuppressive or cytostatic drugs mediate the AdV life cycle. A series of these drugs were tested in AdV- infected human embryonic lung (HEL) cells and A549 cancer cells, to assess their antiviral (or proviral) effect on AdV replication. To this goal, suitable procedures were developed. Virus replication was monitored by (fluorescence) microscopy, cell viability assay and qPCR for viral DNA. Anti-AdV activity was observed for the immunosuppressants sirolimus and methotrexate, and reference antiviral agent cidofovir. Sirolimus was only active in HEL cells. An attempt was made to implement an ELISA assay for mTOR pathway activity, the target of sirolimus. More research is needed to understand the different impact of sirolimus on AdV infection in the two cell lines. The results indicate that some immunosuppressants can modulate AdV replication. Besides, the methods developed are relevant for ongoing anti-AdV drug discovery projects.