The anti-viral immune response of the adult host robustly modulates neural stem cell activity in spatial, temporal, and sex-specific manners

Abstract

Viruses induce a wide range of neurological sequelae through the dysfunction and death of infected cells and persistent inflammation in the brain. Neural stem cells (NSCs) are often disturbed during viral infections. Although some viruses directly infect and kill NSCs, the antiviral immune response may also indirectly affect NSCs. To better understand how NSCs are influenced by a productive immune response, where the virus is successfully resolved and the host survives, we used the CD46+ mouse model of neuron-restricted measles virus (MeV) infection. As NSCs are spared from direct infection in this model, they serve as bystanders to the antiviral immune response initiated by selective infection of mature neurons. MeV-infected mice showed distinct regional and temporal changes in NSCs in the primary neurogenic niches of the brain, the hippocampus and subventricular zone (SVZ). Hippocampal NSCs increased throughout the infection (7 and 60 days post-infection; dpi), while mature neurons transiently declined at 7 dpi and then rebounded to basal levels by 60 dpi. In the SVZ, NSC numbers were unchanged, but mature neurons declined even after the infection was controlled at 60 dpi. Further analyses demonstrated sex, temporal, and region-specific changes in NSC proliferation and neurogenesis throughout the infection. A relatively long-term increase in NSC proliferation and neurogenesis was observed in the hippocampus; however, neurogenesis was reduced in the SVZ. This decline in SVZ neurogenesis was associated with increased immature neurons in the olfactory bulb in female, but not male mice, suggesting potential migration of newly-made neurons out of the female SVZ. These sex differences in SVZ neurogenesis were accompanied by higher infiltration of B cells and greater expression of interferon-gamma and interleukin-6 in female mice. Learning, memory, and olfaction tests revealed no overt behavioral changes after the acute infection subsided. These results indicate that antiviral immunity modulates NSC activity in adult mice without inducing gross behavioral deficits among those tested, suggestive of mechanisms to restore neurons and maintain adaptive behavior, but also revealing the potential for robust NSC disruption in subclinical infections.

Keywords: Antiviral immune response; B cells; CD8+ T cells; Hippocampus; Measles virus; Neural stem cells; Neurogenesis; Neurotropic; Proliferation; Subventricular zone; Virus.