Coxsackievirus Targets Proliferating Neuronal Progenitor Cells in the Neonatal CNS

Abstract

Type B coxsackieviruses (CVB) frequently infect the CNS and, together with other enteroviruses, are the most common cause of viral meningitis in humans. Newborn infants are particularly vulnerable, and CVB also can infect the fetus, leading to mortality, or to neurodevelopmental defects in surviving infants. Using a mouse model of neonatal CVB infection, we previously demonstrated that coxsackievirus B3 (CVB3) could infect neuronal progenitor cells in the subventricular zone (SVZ). Here we extend these findings, and we show that CVB3 targets actively proliferating (bromodeoxyuridine ϩ , Ki67 ϩ ) cells in the SVZ, including type B and type A stem cells. However, infected cells exiting the SVZ have lost their proliferative capacity, in contrast to their uninfected companions. Despite being proliferation deficient, the infected neuronal precursors could migrate along the rostral migratory stream and radial glia, to reach their final destinations in the olfactory bulb or cerebral cortex. Furthermore, infection did not prevent cell differentiation, as determined by cellular morphology and the expression of maturation markers. These data lead us to propose a model of CVB infection of the developing CNS, which may explain the neurodevelopmental defects that result from fetal infection.

Distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system

“…14 GFP-CVB3 protein expression was also found in the SVZ at these time points. Previously, we identified infected nestin þ NPSCs in the SVZ following GFP-CVB3 inoculation 20,32 at early time points. By 48 h PI, GFP-CVB3 protein expression was less evident in the choroid plexus and infection spread into the parenchyma of the brain including neurons in the retrosplenial cortex, the rostral migratory stream, olfactory bulb, and hippocampus ( Figure 1l).…”

“…20,26,32 However, the progenitor cell type supporting LCMV infection has not been clearly evaluated by immunofluorescence microscopy utilizing informative cell markers. Therefore, we carefully inspected the tropism and virus (d, h) Similar to LCMV, GFP-CVB3 infection targeted the choroid plexus.…”

“…The procedure for intracranial (ic) inoculation of 1-day-old pups has been described previously. 20,23 Young pups were killed by halothane treatment followed by immediate decapitation at 12, 24, and 48 h PI. Older pups (10 days and beyond) were killed by halothane treatment followed by cervical dislocation.…”

“…18 Despite considerable inherent dissimilarities between CVB3 and LCMV, including differences in T-cell activation, the presence or absence of a lipid bilayer, and substantial differences in virus replication, both viruses appeared to target neural progenitor and stem cells (NPSCs) in the CNS. [19][20][21] Our laboratory has previously shown that CVB3 preferentially targets NPSCs in culture and in the neonatal host presumably owing to their undifferentiated status and high proliferative index. 20,[22][23][24] In addition, we described the recruitment of unique nestin þ myeloid cells into the CNS following CVB3 infection.…”

“…[19][20][21] Our laboratory has previously shown that CVB3 preferentially targets NPSCs in culture and in the neonatal host presumably owing to their undifferentiated status and high proliferative index. 20,[22][23][24] In addition, we described the recruitment of unique nestin þ myeloid cells into the CNS following CVB3 infection. 14 These cells were highly susceptible to infection and assisted in the dissemination of infectious virus into the neurogenic regions of the neonatal CNS at early time points.…”