Virus control within the CNS
About this project
Even though virus infection of the central nervous system (CNS) is a relatively rare event, it causes high morbidity and mortality. Currently, efficacious therapies are very limited due to an incomplete understanding of molecular processes underlying anti-viral control and pathogenesis within the CNS. Upon intranasal instillation, VSV infects olfactory sensory neurons within the nasal epithelium and then moves within the axons into peripheral areas of the olfactory bulb (Detje et al., 2009). There, primarily astrocytes produce type I IFN that protects against lethal encephalitis (Detje et al., 2015). Between day 3 and 6 after infection microglia gets activated and proliferates in the olfactory bulb and accumulates in peripheral areas to form an innate immune shield. Interestingly, type I IFN receptor signaling of astrocytes and neurons is needed in order to obtain full microglia activation. Upon depletion of microglia, or after partial microglia activation, virus dissemination proceeds, which results in lethal encephalitis (Chhatbar et al., 2018). More recently we discovered that amongst day 6 infiltrating leucocytes CD8+ T cells are critically required to promote survival. We found that redundant RIG-I like receptor (RLR) and Toll-like receptor (TLR) signaling confers the induction of IFN-β responses within the brain, whereas only TLR signaling of astrocytes and neurons is needed to recruit leucocytes to the brain. Currently we are analyzing how herpes simplex virus type I (HSV) is sensed within the CNS and how type I interferon responses trigger protective immunity against this virus (Helmholtz Zukunftsthema “Immunology and Inflammation”).
Viral encephalitis often is associated with acute seizures and epilepsy resulting from hippocampal neurodegeneration. The relative roles of microglia versus monocytes in the development of seizures and epilepsy after viral encephalitis are only incompletely understood. In collaboration with Prof. Löscher, Institute for Pharmacology, Veterinary School Hannover, we are using genetic as well as pharmacological approaches to understand the role of microglia and monocytes in seizure development and hippocampal damage. Our studies show that infiltration of monocytes in the CNS after viral encephalitis is involved in seizure development, but does not seem to contribute to hippocampal damage (Waltl et al., 2018). Interestingly, lack of CCR2 and CX3CR1, two chemokine receptors that regulate the responses of monocytes and microglia, results in prevention of hippocampal damage, but not seizure development. Thus seizure development and hippocampal damage after viral encephalitis are outcomes of complex interactions between CNS cells, including microglia and infiltrating monocytes, and associated CNS inflammation due to encephalitis (Kaeufer et al., 2018).
