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Interaction of DCs and viruses

Interaction of DCs and viruses

Project manager: Dr. Alexandra Birzer

This research group focuses on the interaction of DCs and specific viruses, including HSV-1/2 and HCMV. To induce potent immune responses against pathogens, e.g. viruses, DCs play a pivotal role. Thus, it is not surprising that many viruses developed specific immune-escape mechanisms, during their coevolution with the host. We are particularly interested to elucidate the molecular mechanisms leading to such immune escape strategies. In this regard we recently reported, that both adhesion and migration of human DCs, are targeted by herpes simplex virus type-1 (HSV-1) and HSV-2. Enhanced DC-adhesion leads to impaired migration of these cells into the draining lymph nodes and subsequently to reduced anti-viral immune responses.

Moreover, we discovered that HSV-1 specifically modulates the IL-6 signaling pathway in human mDCs. Using phenotypic FACS analyses we showed that IL-6 receptor surface expression was strongly impaired on directly HSV-1-infected mDCs. Surprisingly this was also the case when we analyzed uninfected, bystander mDCs. This is facilitated so-called non-infectious light (L)-particles, which in comparison to infectious heavy (H)-particles, do not contain the viral capsid and thus miss the viral genome. However, they contain many viral proteins, which are sufficient to down-modulate IL-6 receptor expression on mDCs. To obtain further insights, regarding the precise protein composition of these non-infectious L-particles, we performed mass spectrometry analyses, and compared L-particles with infectious H-particles.

In addition, we are interested in the DC-specific viral replication cycle and compared immature iDCs with mature mDCs, and observed a very interesting difference between these cells.  Surprisingly, only iDCs generate infectious H-particles, while mDCs only facilitate the production of non-infectious L-particles. Mechanistically, we found that in mDCs HSV-1 capsids are trapped within the nucleus, thereby inhibiting the viral replication cycle. In sharp contrast, iDCs facilitate an autophagy dependent degradation of the nuclear lamin layer, and thus induce the completion of the viral replication cycle, leading to the generation of infectious viral particles. This represents a new and very interesting mDC-specific mechanisms, to inhibit viral replication.