The innate immune system represents the first line of defense against infections, and in the case of virus infections, it is believed that the type I interferon (IFN) represents the initial response. However, IFN can also be pathological, and it can seem paradoxical, to have a potentially damaging system as the one activated most frequently. Therefore, the purpose of the project is to explore whether there are innate immune mechanisms which work independet of the IFN system to enable host defense reactions that control viruses but have less inflammatory activity. Identification of such novel immune mechanisms would potentially provide a knowledge basis for novel antiviral therapies. The project is divided into four sections, each exploring one aspect of early innate antiviral defense: (i) identification of mechanisms of immune sensing of viruses at epithelial surfaces; (ii) exploration of the importance and mechanisms of action of tonic IFN signaling, (iii) identification of novel restriction factors; (iv) identification of mechanisms initiating IFN expression during viral infection, including the possible interaction with constitutive immune mechanisms.
Key results from the project include discovery of TMEFF1, HIF1a and the autophagy pathway as central and non-redundant mechanisms exerting early control of HSV infections in epithelial cells and neurons. The project also led to deeper understanding of the signaling mechanisms governing the antiviral interferon response, and mechanisms through which viruses evade these host responses. Finally, the project took advantage of muse models and deep phenotyping omics technologies to uncover and characterize protective and pathological processes in the early immune response to HSV infections.
Altogether, ENVISION has lead to important new understanding of the early events that govern antiviral defense. In addition, the project trained a number of early career scientists, some have remained in academia, and some have moved to a job in the pharma sector. The identified novel antiviral mechanisms, molecules, and pathways could lead to new vaccines, therapeutics, and diagnostic tools for a number of different diseases.
