Project manager: Dr. rer. nat. Linda Grosche
Dendritic cells (DCs) are antigen-presenting cells that play a pivotal role in the induction of protective adaptive immune responses during (viral) infections. The focus of this project group is the identification of virus-specific immune evasion mechanisms during herpesviral infections of DCs, i.e. herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). Regarding this, we have shown that HSV-1 downmodulates the expression of the functionally important surface molecule CD83 on infected mature DCs. Particularly, the immediate-early expressed viral protein ICP0 mediates the proteasome-dependent degradation of CD83, which is, however, independent from the ICP0-inherent E3 ubiquitin ligase function as well as the cellular ubiquitination machinery. Interestingly, the infection of DCs with HCMV also leads to the proteasomal degradation of CD83, with the involvement of the immediate-early expressed viral protein IE2.
An additional HSV-1- and HCMV-mediated immune evasion mechanism is the inhibition of mDC migration. This was shown to be caused, among others, by rapid induction of mDC adhesion. The precise molecular mechanism is currently under investigation. Furthermore, our project group is interested in the characterization of HSV-1 replication in immature DCs versus mature DCs. Contrary to previous hypotheses, we could show that HSV-1 indeed establishes its complete gene expression cascade in mature DCs. However, supernatants of mature DCs, in contrast to those of immature DCs, barely contain any infectious progeny virions, and almost exclusively contain non-infectious L-particles. In this regard, we have proven that HSV-1 capsids are trapped inside the nucleus of mature DCs, while immature DCs facilitate complete replication. Regarding this, our analyses showed that the cellular autophagic degradation of nuclear lamin proteins plays an essential role during the release of infectious virions by immature DCs, whereas this process is inhibited in mature DCs. An additional project deals with the analysis of non-infectious L-particles, due to their ability to transfer functional viral proteins to un-infected bystander cells. Thus, L-particles constitute an additional immune evasion strategy of HSV-1, since they can also modulate bystander cells for the benefit of the virus.