Long-term Protection against a Pathogenic Wild-Type RABV CNS Challenge and the Establishment of Tissue Resident Long-Lived Effector Cells during Immunization

摘要

Current models used to study the formation of immunological memory in the CNS involve artificial induction of blood-brain barrier (BBB) through application of virus via intra-cranially inoculation or by the inflammatory nature of the anti-viral response. Using rabies virus (RABV) variants that spread trans-axonally into CNS tissues without causing damaging immunopathology, we show that CNS resident immune cells are capable of independently clearing a direct CNS challenge infection in the absence of changes in BBB permeability and therefore without further immune cell infiltration from peripheral tissues. The clearance of attenuated RABV from brain tissues by immune cells infiltrating across an altered BBB results in local long-term persistence of rabiesspecific immunity. Upon intranasal challenge with pathogenic rabies virus the CNS resident immune cells mediate a protective response despite the maintenance of BBB integrity. The significance of these results is that long-lived immune effectors resident in brain tissue can independently protect against infection with a virus that reaches the CNS without contributions from peripheral immune mechanisms. Immunizing virus must reach CNS tissues during infection for this long-term protection to be conferred. Consistent immune protection was not seen after immunization protocols where attenuated virus does not reach the CNS. These findings have implications both in RABV vaccine strategies as well as many immunological pathologies within the CNS.