Danish Medical Bulletin - No. 1. February 2004. Vol. 51 Page 144.

Molecular mechanisms of NF- κ B activation during viral infections

Trine Hyrup Mogensen

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This PhD dissertation was accepted by the Faculty of Health Sciences, University of Aarhus, and defended on November 14, 2003.

Official opponents: Niels Ødum, Fernando Arenzana-Seisdedos, France, and Claus Munck Petersen.

Tutors: Per Höllsberg and Svend Birkelund.

Correspondence to: Trine Hyrup Mogensen, Klokkervej 1B, DK-8210 Aarhus V.

Dan Med Bull 2004;51:144.

Abstract

This PhD dissertation is based on studies carried out at the Department of Cancer Biology, The Cleveland Clinic Foundation, Cleveland, USA, and The Department of Medical Microbiology and Immunology, University of Aarhus. The dissertation consists of three original papers and two reviews published in international journals.

During a viral infection, a strong host response is initiated aiming at eliminating the invading pathogen. In this process, the innate immune system provides the first line of defense, which is followed by activation of the adaptive immune system. In recent years, molecular understanding of the virus-host interactions that occur in infected cells has increased, and many signalling pathways and transcription factors activated during a virus infection have been identified. Among these, the transcription factor nuclear factor (NF)-κB plays a pivotal role in initiation and regulation of the proinflammatory response to various different stimuli, including virus infection. Accordingly, NF-κB signalling is activated by several human pathogenic vira, which can induce signalling by multiple mechanisms, including interaction of viral surface proteins with cellular receptors and signaling by viral proteins or double-stranded RNA (dsRNA) produced during the course of the viral life cycle.

The aim of this project was to investigate some mechanisms for activation of NF-κB during virus infections. The first part focused on signalling pathways involved in NF-κB activation by dsRNA and the interferon (IFN) inducible dsRNA-activated kinase PKR. These studies demonstrated that dsRNA-induced signalling proceeds through IκB kinase (IKK) and the upstream kinase NIK. Furthermore, we demonstrated that PKR associates physically with IKK, which together with additional data supports the hypothesis that PKR may play a role in NF-κB activation by the cytokines TNF-α and IFN-γ . The aim of the other part of this dissertation was to investigate mechanisms of NF-κB activation during herpes simplex virus (HSV) infection in macrophages. We demonstrated that NF-κB activation is mediated through IKK and the upstream kinases TAK1, MEKK1, and NIK. Furthermore, the data strongly suggested that mitochondria may function as a cellular checkpoint during HSV infection through the generation of reactive oxygen intermediates and release of calcium.

NF-κB has proven not only to play an essential role in the generation of a proinflammatory response to infections, but also to be involved in acute and chronic inflammatory diseases as well as in the development of malignancy. Knowledge of this transcription factor is therefore important in order to better understand the role of NF-κB in defense and disease.

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