C-type lectin receptor-mediated effects on neurodegeneration and immunopathology in the brain following neurotropic virus infection

点击翻译按钮获取中文摘要

The Theiler's murine encephalomyelitis virus (TMEV) represents a reliable experimental mouse model to study neurodegenerative processes and seizures induced by neurotropic viruses. Antigen presenting cells (APC) account for the initiation of neuroinflammation and neuronal damage in infected C57BL/6 mice. Activating and inhibiting C-type lectin receptors (CLRs) are pattern recognition receptors on APC that tightly control immune homeostasis and protective immunity in different infectious disorders; however, their function in TMEV infection remains as yet undetermined. Based on the hypothesis that dysregulated CLR activation causes brain immunopathology and neurodegeneration, the planned project aims to analyze the effect of CLRs in the neuropathogenesis of TMEV infection in detail. Therefore, (1) viral and/or host specific ligands will be identified and (2) mechanistic studies will be performed to determine the function of CLRs (DCIR, Clec-12a, Dectin-1) and the adaptor protein CARD9 in TMEV-infected mice. Viral and host specific ligands will be identified using a CLR-Fc fusion protein library and CLR reporter cell lines. For analyses of CLR-mediated effector functions on APC upon infection, dendritic cells, macrophages and microglia derived from wild type, CLR-/- and CARD9-/- mice will be stimulated in vitro by viral and/or host specific ligands. Animal infection experiments will be performed to determine DCIR-, Clec-12a-, Dectin-1- and CARD9-mediated effects on neuroinflammation and -pathology using knockout mouse strains. The role of CLR-expressing APC populations in immune regulation and pathogenesis in the TMEV model will be analyzed in mixed bone marrow chimeric mice of CD11b-diphtheria toxin receptor (DTR) and CD11c-DTR transgenic and the respective CLR-/- mouse lines. Results will help to understand the underlying mechanisms of neuroprotection and initiation of degeneration in viral encephalitis and will give detailed insights in the regulation of innate immunity in infectious disorders of the central nervous system.