Coxsackievirus targets proliferating neuronal progenitor cells in the neonatal CNS.
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+, Ki67+) 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.
Feuer
Ralph
R
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Pagarigan
Robb R
RR
Harkins
Stephanie
S
Liu
Fei
F
Hunziker
Isabelle P
IP
Whitton
J Lindsay
JL
D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002552:Cerebral Ventricles / Q000166:cytology / Q000378:metabolism / Q000821:virology; D003384:Coxsackievirus Infections / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000235:genetics / Q000472:pathogenicity*; D005455:Fluorescent Antibody Technique / Q000379:methods; D049452:Green Fluorescent Proteins / Q000378:metabolism; D017403:In Situ Hybridization / Q000379:methods; D007211:Indoles / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D009474:Neurons / Q000502:physiology / Q000821:virology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology / Q000821:virology*; D014404:Tubulin / Q000378:metabolism
D007211:Indoles; D007381:Intermediate Filament Proteins; D019394:Ki-67 Antigen; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D039842:Neural Cell Adhesion Molecule L1; D011991:Receptors, Virus; D012794:Sialic Acids; D014404:Tubulin; C105941:coxsackievirus B receptor; C103469:polysialyl neural cell adhesion molecule; D049452:Green Fluorescent Proteins; C007293:DAPI; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine
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