Interplay of IKKs and IKK-related kinases in antiviral nucleic acid receptor signaling in human monocytes

Abstract

Monocytes and monocyte-derived cells are among the first line of host defense against invading pathogens. They are equipped with pattern recognition receptors (PRRs) that detect conserved components of microbes and in response initiate signaling cascades that result in the production of warning messenger substances like type I interferons (IFNs), chemokines, and proinflammatory cytokines. These mediators contribute decisively to pathogen clearance, as they induce an antiviral state and recruit other immune cells to the site of infection, but may also harm the host if their release is not tightly restricted. The IκB kinases (IKKs) IKKα and IKKβ as well as the IKK-related kinases TBK1 and IKKε control antimicrobial gene transcription by directing the activation of the involved transcription factors of the IFN-regulatory factor (IRF) and NF-κB families and are therefore considered master regulators of PRR signaling. In this thesis, the individual functions of these kinases in different PRR pathways as well as their interplay in human monocytes were defined. The insights that were obtained contribute substantially to the understanding of kinase functions in dysregulated immune responses and in the clearance of viral infections, and the discovered mechanisms add new connections to the complex network of signaling pathways downstream of PRRs.