Our organism is constantly bombarded with countless pathogens, yet we are relatively healthy. This is partially due our immune system, which recognises and destroys most invaders with only few of them escaping and causing illness. The pathogenicity of viruses is determined by virus-host interactions that occur at various sites: (1) cellular proteins sense incoming viruses and either trigger alarm signals (e.g. cytokines) or are directly involved in destruction of pathogens. (2) The alarm signals induce changes in the cellular composition of proteins that execute an antiviral program. (3) Viral gene products perturb the initiation or the execution of the immune response by targeting central points in the antiviral cascade.
My lab is generally interested in the interaction of viral structures (proteins and nucleic acids) with host factors and the relevance for antiviral immunity. We aim to get functional and mechanistic insights in the interplay between viruses and the organism by studying virus-host interactions and protein expression profiles that are elicited by viral infections. Through this approach identify yet unstudied proteins and pathways that we are further testing in focused hypothesis-driven approaches that include testing of interactions on molecular basis, in vitro cell culture assays and in vivo models using genetically modified animals.
We identified viral triphosphorylated RNA as specific ligand for the virus sensor RIG-I (Pichlmair et al., Science 2006). Using affinity proteomics followed by mass spectrometry we identified additional proteins binding specifically to this type of RNA. Interferon induced proteins with tetratricopeptide repeats (IFIT), for instance, bind PPP-RNA and perturb virus growth (Pichlmair et al, Nature Immunology, 2011). IFIT proteins bind PPP-RNA using a uniqe mechanism ensuring high specificity and affinity (Abbas et al., Nature 2013). IFIT1 depletion in vitro and in mice are specifically susceptible to infection with viruses including orthomyxo- (e.g. influenza A virus) and paramyxoviruses (e.g. vesicular stomatitis virus). Functionally, IFITs specifically target translation of viral RNA (Habjan et al., Plos Pathogens, 2013). Using similar approaches we identified a yet unstudied protein, NCBP3, as cap-binding protein (Gebhardt et al., Nature Communications 2015). NCBP3 binds NCBP1 to from an alternative Cap-RNA complex (CBC) that binds to mRNA and is important for RNA processing and export. Lack of NCBP3 is increasing vulnerability to virus infections, suggesting an important role of the alternative CBC during antiviral responses.
Though comprehensive knowledge on changes in the transcriptome, comparable little is known on the global changes of the proteome after infection with individual viruses. We are assessing virally-induced changes in the global composition of the proteome as well as specific post-translational modifications.
Viruses require the host cellular machinery to replicate. We use viruses go guide us to cellular proteins and pathways that are determining virus pathogenicity. To this aim we are using mass spectrometry to study cellular binding partners of viral proteins using systems biology approaches (Pichlmair et al., Nature 2012). We identified 600 cellular proteins that are binding to of viral immune modulators (iVIMs). We are now complementing this survey to assess the functional consequences for antiviral immunity. This survey so led to identification of novel modes of transcriptional regulation by an orthomyxovirus that specifically affects genes required for host defense (Haas et al., Plos Pathogens, 2018). Furthermore, we identified a novel cell death pathway named Oxeiptosis that is targeted by viral proteins derived from diverse viruses. Intracellular reactive oxygen species (ROS) that are commonly generated during virus infections, engagement of toxic substances or teratogenic transformation of cells (Holze et al., Nature Immunology, 2018). The cellular protein KEAP1 senses increased ROS levels and activates a cell death cascades that involves the mitochondrial enzyme PGAM5 that dephosphorylates the protein AIFM1. This leads to cell death. Lack of oxeiptosis in mice induces hyperinflammation after virus infection, which is associated to increase immunopathology.
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