Pathogen-induced Expression of IFNs and ISGs

Innate immune recognition is mediated by a system of germline-encoded receptors (Toll receptors, TLRs) that recognize conserved molecular patterns associated with microbial pathogens. These receptors, which are coupled to downstream signaling cascades that mediate the induction of immune-response genes, represent the most ancient host defense system found in mammals, insects and plants.
In mammals, these host-response factors include the interferons, which exert their antimicrobial effects through the induction of a set of Interferon Stimulated early response Genes (ISGs). We have previously shown that viral infection as well as TLR stimulation results in ISG-activation, which is mediated by the Interferon Regulatory Factor 3 (IRF3). In addition, several other laboratories reported IRF3 activation in response to ss or dsRNA, CpG-DNA and DNA-damaging agents. The goal of this project is the deliniation of the signaling events that lead to IRF3-mediated transcriptional induction after pathogen recognition. Our most recent findings demonstrate that TLRs utilize Ca2+  and Reactive Oxygen Species (ROS) for IRF3-mediated induction of ISGs, and further implicate ASK1 and ATM family  kinases in the process. In addition, we have identified a novel family of host-cell proteins that function as cytoplasmic pathogen sensors.

Micro-RNAs in the Mammalian Host Defense

RNA interference through non-coding microRNAs (miRs) represents a vital component of the innate antiviral immune response in plants and invertebrate animals, however, a role for cellular miRs in the defense against viral infection in mammalian organisms has thus far remained elusive. We found that interferons or TLR activation rapidly modulates the expression of numerous cellular miRs. Several of these IFN-induced miRs have predicted targets within viruses such as hepatitis C virus (HCV), HIV, Influenza or Dengue virus. We recently demonstrated the antiviral activity of several cellular miRs against HCV infection. There, introduction of synthetic miR-mimics corresponding to these IFN-induced miRs reproduces the antiviral effects of IFN on HCV replication and infection, whereas neutralization of these antiviral miRs reduces the antiviral efficacy of IFN. We are currently investigating the antiviral capacity of the IFN-induced miRs against several other viruses. Taken together, our findings strongly support the notion that mammalian organisms too, via the interferon system, utilize cellular miRs to combat viral infections.

Interferons and Autoimmune Disorders

Interleukin 2 (IL-2) is powerful mitogen for T cells, and its production is a hallmark of T cell activation. As such, much emphasis has been placed on the elucidation of the mechanism by which T cell receptor engagement leads to the transcriptional induction of the IL-2 gene. In comparison, much less is known about the processes that lead to the suppression of such IL-2 production by intervening signaling events. We recently discovered that IFNb potently inhibits IL-2 production of activated human and murine T cells, which offers a possible mechanism for the beneficial effects of IFNs in autoimmune diseases such as Multiple Sclerosis.
Furthermore, we had discovered that mice lacking the IFN-activated transcription factor STAT1 are highly susceptible to autoimmune disease, suggesting an important role of STAT1 in the development and activation of T cells. We reasoned that STAT1-deficiency leads to a defect in the elimination of autoreactive T cells via apoptosis, and we indeed found that both positive and negative selection of T cells are severely impaired in STAT1-deficient animals. As STAT1 is a prominent target for virus-mediated degradation, these observations offer an intriguing model for the development of autoimmune diseases after viral infections.