Enforced virus replication as an immunological mechanism for immune activation during viral infection

• Antragsteller: Professor Dr. Karl Sebastian Lang
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2012 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 227741262

The innate immune system limits virus replication by type I interferon (IFN-I) and also induces the presentation of viral antigens to adaptive immune cells. Using a mouse model of a highly cytopathic virus (vesicular stomatitis virus [VSV]), we investigated the means by which the innate immune system inhibits virus propagation but still allows the presentation of antigen to adaptive immune cells. We found that the expression of Usp18 in CD169+ macrophages reduces their responsiveness to type I interferon (IFN-I), thereby allowing locally restricted replication of virus. This enforced virus replication is essential to the induction of adaptive antiviral immune responses and, therefore, to the prevention of fatal outcome after infection.In the proposed studies we will investigate in more detail the mechanism of enforced virus replication in dendritic cells (DCs) and CD169+ macrophages. We will determine the importance of Socs1 and Socs3 in the process of enforced virus replication. We will use a persistence-prone non-cytopathic virus (lymphocytic choriomeningitis [LCMV]) to investigate the role of enforced virus replication in the induction of T cells with antiviral adaptive memory T cells and in the development of T-cell exhaustion. We will also use a model of autoimmune diabetes (transgenic mice that express LCMV under the control of the rat insulin promoter [RIP-GP mice]) to study the role of enforced virus replication in immunological tolerance and ignorance. The proposed research will thus characterize the mechanisms underlying enforced virus replication and the impact of these mechanisms on viral infection and autoimmunity.

• DFG-Verfahren: Sachbeihilfen