title: 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+, 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.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Feuer
authors.forename: Robb R
authors.initials: RR
authors.lastname: Pagarigan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Harkins
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Isabelle P
authors.initials: IP
authors.lastname: Hunziker
authors.forename: J Lindsay
authors.initials: JL
authors.lastname: Whitton
mesh_terms: 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
chemical_list: 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
references.citation: Cell. 1999 Jun 11;97(6):703-16
references.pmid: 10380923
references.citation: Am J Pathol. 1999 Oct;155(4):1205-15
references.pmid: 10514403
references.citation: Nat Med. 2000 Apr;6(4):429-34
references.pmid: 10742150
references.citation: J Virol. 2000 May;74(9):4284-90
references.pmid: 10756043
references.citation: Brain Res Mol Brain Res. 2000 Apr 14;77(1):19-28
references.pmid: 10814828
references.citation: J Pathol. 2000 Jul;191(3):286-98
references.pmid: 10878551
references.citation: Infection. 2000 Sep;28(5):326-8
references.pmid: 11073143
references.citation: Mod Pathol. 2000 Nov;13(11):1200-5
references.pmid: 11106077
references.citation: Nature. 2001 Feb 8;409(6821):714-20
references.pmid: 11217860
references.citation: Nat Rev Neurosci. 2001 Apr;2(4):287-93
references.pmid: 11283751
references.citation: J Neurosci. 2001 Nov 1;21(21):8505-13
references.pmid: 11606639
references.citation: Nature. 2001 Nov 1;414(6859):112-7
references.pmid: 11689956
references.citation: Obstet Gynecol. 2001 Dec;98(6):1019-26
references.pmid: 11755547
references.citation: J Virol. 2002 Apr;76(7):3365-73
references.pmid: 11884562
references.citation: J Virol. 2002 May;76(9):4430-40
references.pmid: 11932410
references.citation: J Neurosci. 2002 Apr 15;22(8):3161-73
references.pmid: 11943818
references.citation: J Neurosci. 2002 May 1;22(9):3568-79
references.pmid: 11978833
references.citation: Chem Senses. 2002 Jul;27(6):577-80
references.pmid: 12142335
references.citation: Neurosci Res. 2002 Dec;44(4):467-73
references.pmid: 12445634
references.citation: J Virol. 2003 Jan;77(1):1-9
references.pmid: 12477805
references.citation: Brain Res Dev Brain Res. 2003 Jun 12;143(1):1-13
references.pmid: 12763576
references.citation: Med Microbiol Immunol. 2004 May;193(2-3):83-90
references.pmid: 12925877
references.citation: Am J Pathol. 2003 Oct;163(4):1379-93
references.pmid: 14507646
references.citation: Curr Opin Genet Dev. 2003 Oct;13(5):543-50
references.pmid: 14550422
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15906-11
references.pmid: 14673080
references.citation: J Comp Neurol. 2004 Feb 9;469(3):311-24
references.pmid: 14730584
references.citation: Development. 1992 Sep;116(1):201-11
references.pmid: 1483388
references.citation: J Pediatr. 2004 Mar;144(3):316-20
references.pmid: 15001934
references.citation: Cell. 1990 Feb 23;60(4):585-95
references.pmid: 1689217
references.citation: Clin Perinatol. 1988 Jun;15(2):233-46
references.pmid: 2837356
references.citation: J Comp Neurol. 1989 Jan 22;279(4):567-80
references.pmid: 2918088
references.citation: Brain Res Dev Brain Res. 1988 Nov 1;44(1):95-108
references.pmid: 3069243
references.citation: Cell Tissue Kinet. 1986 Mar;19(2):179-82
references.pmid: 3698075
references.citation: Med Clin North Am. 1985 Mar;69(2):399-413
references.pmid: 3990441
references.citation: Prog Med Virol. 1973;15:42-62
references.pmid: 4572439
references.citation: Rev Infect Dis. 1983 Nov-Dec;5(6):1019-32
references.pmid: 6318288
references.citation: J Neurosci. 1997 Jul 1;17(13):5046-61
references.pmid: 9185542
references.citation: J Paediatr Child Health. 1998 Apr;34(2):196-8
references.pmid: 9588649
references.citation: Am J Pathol. 1998 Aug;153(2):417-28
references.pmid: 9708802