Detection of viral invasion by pattern recognition receptors (PRR) is key for the induction of a rapid immune response and early control of infection. PRR sense viral nucleic acids and activate signaling cascades culminating in the transcription of type I interferons (IFN) and proinflammatory cytokines. Since this potent antiviral immune response restricts viral propagation, herpesviruses have in turn evolved a range of mechanisms targeting virtually every step of PRR signaling to overcome their clearance by the immune system. Herpesviruses can even use PRR signaling for their own benefit, which adds another layer of complexity to the fine-tuned interplay between herpesviruses and their host.

Viral tegument proteins that are introduced into infected cells with the incoming virions are prime candidates for PRR antagonists: they are present from the beginning and can act promptly on PRR signaling. Based on our previous work on herpesviral PRR antagonists, we will decipher the molecular mechanisms how the tegument proteins M35, UL35, and UL82 of cytomegalovirus (CMV) interfere with type I IFN induction in the nucleus, and how this affects cellular and viral transcription.

The tegument proteins of human CMV (HCMV), UL35 and UL82, co-localize in close proximity to promyelocytic leukemia nuclear bodies (PML-NBs) early in infection, and it is known that UL82 interacts with the PML-NB client DAXX. Hence, we will decipher the contribution of different protein components of PML-NBs for IFNB1 transcription upon HCMV infection, and will expand this focus together with other members of this research unit. This project will deepen our knowledge about the manifold facets of CMV evasion of the innate immune response, and thereby provide novel insights into cellular determinants important for IFNB1 transcription and progression of infection.