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The unique anatomy of the central nervous system (CNS) necessitates that
inflammation in this organ is limited. However, emerging studies reveal that focal
inflammation may be more prominent than previously appreciated. Avenues for
immune surveillance and antigen drainage from the CNS have recently been
elucidated, and suggest a framework whereby memory T cells engage viral antigen
either at the CNS peripheries or in draining lymph nodes. Such surveillance schemes
may offer insufficient or too delayed control of a rapidly replicating virus, and fail to
incorporate a role for B cells that critically orchestrate immunological memory to
viruses. Intriguingly, in mice and humans, certain latent viral infections induce the
formation of memory lymphocytic clusters that may play a role in local
immune-surveillance. The prevalence of these structures associated with different
neurotropic viral infections, their cellular composition, the cues guiding their
recruitment and retention, and finally their functions in controlling chronic viral
infection are not clear.
The overarching aim of this project is to dissect the function of immune-stimulating
fibroblasts in governing virus- and myelin- specific immune responses during chronic
neurotropic viral infection. Stromal cells secreting immune-stimulating chemokines
and cytokines underpin lymphocytic clusters in chronic inflammatory conditions, such
as the CNS autoimmune disease Multiple Sclerosis (MS) and its animal models. Recent
studies using the neurotropic murine hepatitis virus (MHV) reveal that
immune-stimulating stromal cells are also activated in the CNS during acute viral
infections. Here, I propose to use chronic MHV infection to elucidate the role of
immune-stimulating fibroblasts in orchestrating lymphocytic niches that contribute to
immune-surveillance in the CNS. In order to track and manipulate a defined subset of
immune-stimulating fibroblasts that underpins virus-induced lymphocytic niches, I
will employ highly specialized mouse models generated by the host lab. Using these
tools in combination with genetic and pharmacological studies, I will define the
function of a specific subset of immune-stimulating fibroblasts activated during
chronic MHV infection (aim 1), dissect the mechanism of antigen-dependent memory B
cell responses in the CNS (aim 2), and assess the capacity for immune-stimulating
fibroblasts to promote the cross-activation of myelin-specific T cells, thereby prompting
CNS autoimmunity (aim 3). Moreover, the capacity for other neurotropic viruses to
induce immune-stimulating fibroblastic stromal cell niches, and promote the
cross-activation of myelin-specific T cells, will be assessed to determine whether these
are shared host responses to chronic neurotropic viral infections.
This study proposes a paradigm shift to the current dogma of immune surveillance in
the CNS, which fails to incorporate immune-stimulating fibroblasts and memory B
cells. A thorough understanding of the processes that control chronic neurotropic viral
infections is critical in order to design improved immune therapies that prevent viral
recrudescence, as has been observed in MS. Moreover, since the mechanism by which
viral infections exacerbate MS remains unclear, these studies will shed light on
whether a virus-induced immune-stimulating microenvironment favours the
cross-activation of myelin-specific T cells. Collectively, this research will provide a more
thorough understanding of the mechanisms controlling viral infections and CNS
autoimmunity