Identification and manipulation of immune-stimulating fibroblastic stromal cell niches in the
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, which 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 study the role of immune-stimulating fibroblasts in orchestrating immune-competent 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-reactive T cells, thereby prompting CNS autoimmunity (aim 3). Moreover, the capacity for other neurotropic viruses to induce immune-stimulating fibroblastic stromal cell niches, or promote the cross-activation of myelin-reactive 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 for designing 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.
|type of project||fundamental research|
|status||ongoing - recruiting phase|
|start of project||2019|
|end of project||2022|
|project manager||Dr. Natalia Pikor|