Adult neurogenesis is a tightly regulated process emanating from two specific brain regions: the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) along the lateral ventricle. Neural stem cells within these two zones can both self-renew and generate astrocytes, oligodendrocyte progenitors, or neuronal progenitor cells (NPCs). These NPCs provide a source of new neurons for neuron turnover, repair from injury, and hippocampal plasticity - an essential component of proper learning and memory. Many of the molecules that cue NPCs to proliferate, migrate, and differentiate are also utilized by the adult immune system to control and direct leukocytes in response to a pathogenic infection. For example, CXCL12 and CXCR4 are molecules that form a chemokine ligand-receptor pair that both directs migration and proliferation of NPCs and regulates the extravasation of leukocytes across the blood brain barrier in response to CNS pathogens. West Nile virus (WNV), a flavivirus now endemic in North America, is one of several viruses that are able to enter the CNS, infect neurons, and cause encephalitis. Of interest, many patients who recover from WNV encephalitis report cognitive sequelae, including memory impairments and depression, which may last years beyond the episode of infection. WNV encephalitis induces activation of immune responses in resident neurons and glia, leading to upregulation of chemokines and cytokines that recruit leukocytes, but may also influence proliferation, migration, and fate of NPCs. In particular, chemokine expression patterns that are altered at perivascular spaces to promote leukocyte entry may impact the homeostasis of NPCs, which use perivascular spaces within neurogenic zones as a trophic niche and migratory scaffold. The effects of WNV encephalitis on adult NPC homeostasis have not been previously investigated. In preliminary studies using an established adult murine model of WNV encephalitis in conjunction with in vivo BrdU labeling, we observed fewer newly generated neuroblasts, more newly generated astrocytes, aberrant neuroblast migration, and changes in the expression and vascular localization of CXCL12 at the peak of acute CNS infection. NPCs do not appear to be infected or killed by WNV, suggesting that WNV infection affects extrinsic proliferation and/or migratory cues received by progenitor cells. Such alterations in NPC proliferation, migration, and cell fates could alter the brain's ability to repair itself from damage and lead to learning an memory impairments. Within this proposal, we will first determine how alterations in NPC biology impact on hippocampal neurogenesis during and after WNV encephalitis. Second, we will determine how CXCL12-CXCR4 signaling modulates NPC homeostatic changes during WNV encephalitis. The goal of this proposal is to acquire mechanistic knowledge regarding how viral encephalitis induces effects on NPC homeostasis. Furthermore, knowledge about the behavior of neural stem cells within inflamed conditions may help guide the development of stem cell-based therapeutics for other CNS diseases with inflammation.
|Sun, Tony; Vasek, Michael J; Klein, Robyn S (2014) Congenitally acquired persistent lymphocytic choriomeningitis viral infection reduces neuronal progenitor pools in the adult hippocampus and subventricular zone. PLoS One 9:e96442|