The innate immune system dynamically responds to infecting pathogens by initiation of protective host responses and by a rapid termination of these responses once the infection agent is no longer present. Inefficient or uncontrolled responses may result in infectious or inflammatory diseases. We investigate both the basic principles of balanced innate immune responses as well as aspects relevant for immune disorders. The molecular mechanisms that allow a robust yet temporally precisely restricted inflammatory reaction are studied in our laboratory at the level of transcription, mRNA stability and pathogen recognition.

Turning on/off and resetting inflammatory gene transcription

The Stat transcription factors play a central role in the immune system. An open question is the molecular mechanism that determines how often one activated Stat molecule can initiate transcription before becoming inactivated. Our recent studies revealed that phosphorylation at serine 727, an important modification of Stat1, is restricted only to promoter-bound Stat1 molecules. This suggests that the still not well understood S727 kinase is a chromatin-associated enzyme involved in the feedback control of the transcription cycle at the targeted gene. We are currently characterizing the kinases and their role in the Stat-dependent transcription cycle.

Control of immune homeostasis by mRNA stability

A considerable proportion of the genes induced during the acute phase of inflammation are strongly regulated at the level of mRNA stability. Many proinflammatory mRNAs contain in their 3´ untranslated regions cis-acting AU-rich regulatory elements (AREs) that are targeted by RNA-stabilizing and -destabilizing proteins. The RNA-destabilizing protein tristetraprolin (TTP) plays a fundamental role in the attenuation of inflammation. Our newest findings revealed that TTP is one of the effector molecules of the anti-inflammatory cytokine IL-10. We are currently studying the role of TTP in inflammatory diseases using animals with conditional ablation of the TTP gene.

Responses of innate immune cells to Streptococcus pyogenes

S. pyogenes is a Gram-positive human pathogen causing mild (e.g. tonsillitis) as well as severe (e.g. toxic shock) diseases. It is still not known how this bacterium is recognized by the innate immune system. We have recently shown that, surprisingly, S. pyogenes is recognized by a receptor that is distinct from any so far described receptors for bacterial pathogens. The identification of the receptor for S. pyogenes and the elucidation of inflammatory signaling cascades in the host cells are currently the major goals of the project.