Modulation of cellular IKK complexes by human Adenovirus Type 5 ; Modulation des zellulären IKK-Komplexes im produktiven Replikationszyklus des humanen Adenovirus Typ 5

Human Adenoviruses (HAdV) employ various strategies to interfere with the innate and the adaptive host immune response. Therefore, they encode multiple proteins especially the early proteins, which are capable to inhibit the expression of interferon-stimulated genes (E1A, VA-RNA), certain proinflammatory cytokines such as IL-6 (E1A) and down-regulation of MHC class I molecules (E3). The complexity of regulation by adenoviruses is obvious in regard to TNFα. The early HAdV-C5 protein E1A sensitizes cells to TNFα induced apoptosis, which is in turn counteracted by products of the E3 region and E1B-19K. Further, many publications applying adenovirus vectors show cell line-dependent activation of different subsets of cytokines, which are activated by NF-κB. However, the mechanism of NF-κB pathway modulation in lytic infection is yet unknown and hence was investigated in the present study. The results presented here show for the first time that HAdV-C5 infection inhibits TNFα mediated NF-κB activation in human non-small cell lung carcinoma cells (H1299) during the late phase of infection. This is presumably mediated by attenuated IκB kinase (IKK) complex formation comprising the proteins IKKα, IKKβ and NEMO upon adenoviral infection. Furthermore, E1B- 55K interacts with IKKα of the IKK complex that is relocalized into the nucleus juxtaposed to viral replication centers in an E1B-55K-independent manner. However, NEMO is relocalized into viral replication centers and counteracts E1B-55K expression levels. Results presented here show that both host factors IKKα and NEMO promote efficient adenoviral gene expression and replication representing proviral factors of the IKK complex. Taken together, data obtained during this thesis show that HAdV-C5 is able to inhibit TNFα-mediated NF-κB activation and that the virus benefits from processes sequestering NEMO and IKKα into the nucleus in order to promote viral life cycle. ; Humane Adenoviren (HAdV) haben im Laufe der Evolution vielfältige Strategien entwickelt, um sowohl die ...