Murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain.
BACKGROUND
Congenital cytomegalovirus (CMV) brain infection causes serious neuro-developmental sequelae including: mental retardation, cerebral palsy, and sensorineural hearing loss. But, the mechanisms of injury and pathogenesis to the fetal brain are not completely understood. The present study addresses potential pathogenic mechanisms by which this virus injures the CNS using a neonatal mouse model that mirrors congenital brain infection. This investigation focused on, analysis of cell types infected with mouse cytomegalovirus (MCMV) and the pattern of injury to the developing brain.


RESULTS
We used our MCMV infection model and a multi-color flow cytometry approach to quantify the effect of viral infection on the developing brain, identifying specific target cells and the consequent effect on neurogenesis. In this study, we show that neural stem cells (NSCs) and neuronal precursor cells are the principal target cells for MCMV in the developing brain. In addition, viral infection was demonstrated to cause a loss of NSCs expressing CD133 and nestin. We also showed that infection of neonates leads to subsequent abnormal brain development as indicated by loss of CD24(hi) cells that incorporated BrdU. This neonatal brain infection was also associated with altered expression of Oct4, a multipotency marker; as well as down regulation of the neurotrophins BDNF and NT3, which are essential to regulate the birth and differentiation of neurons during normal brain development. Finally, we report decreased expression of doublecortin, a marker to identify young neurons, following viral brain infection.


CONCLUSIONS
MCMV brain infection of newborn mice causes significant loss of NSCs, decreased proliferation of neuronal precursor cells, and marked loss of young neurons.
Neuroimmunology Laboratory, Department of Medicine, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, Minnesota, United States of America.
Manohar B
MB
Mutnal
Maxim C-J
MC
Cheeran
Shuxian
S
Hu
James R
JR
Lokensgard
D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000254:growth & development / Q000473:pathology / Q000821:virology*; D001927:Brain Diseases / Q000378:metabolism / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D005434:Flow Cytometry; D006566:Herpesviridae Infections; D051379:Mice; D018146:Muromegalovirus; D058953:Neural Stem Cells / Q000821:virology*; D055495:Neurogenesis
D015415:Biomarkers
Cell. 1998 Jan 9;92(1):63-72
9489700
J Neurosci Res. 2007 Feb 1;85(2):250-9
17131412
Cancer Res. 2009 Jan 15;69(2):431-9
19147555
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14720-5
11121071
J Virol. 2002 Sep;76(17):8842-54
12163604
Mol Cell Neurosci. 2005 Mar;28(3):462-74
15737737
Perspect Pediatr Pathol. 1981;6:203-41
6275339
Pathol Int. 1995 Feb;45(2):91-102
7742931
Cell. 2007 Jun 29;129(7):1377-88
17604725
J Virol. 2004 Jul;78(14):7319-28
15220405
Stem Cells. 2009 Dec;27(12):2928-40
19725119
Congenit Anom (Kyoto). 2009 Jun;49(2):47-55
19489954
Stem Cells. 2007 Jun;25(6):1560-70
17332513
J Infect Dis. 2004 Jul 15;190(2):216-26
15216454
J Neurovirol. 2008 Oct;14(5):437-47
18937121
Neuron. 2001 Aug 16;31(3):367-79
11516395
Nat Rev Neurosci. 2006 Mar;7(3):179-93
16495940
Mol Neurobiol. 2004 Aug;30(1):49-76
15247488
Neuron. 2002 Aug 29;35(5):865-75
12372282
J Neurosci. 2002 Feb 15;22(4):1316-27
11850459
Aging Cell. 2005 Aug;4(4):197-207
16026334
J Neurosci. 2002 May 1;22(9):3594-607
11978835
PLoS One. 2008;3(10):e3469
18941626
Stem Cells. 2007 Sep;25(9):2257-68
17588935
Clin Chem. 2002 Oct;48(10):1819-27
12324512
Nature. 2001 Aug 16;412(6848):736-9
11507641
Nat Med. 2006 Nov;12(11):1237-8
17088886
Cancer Res. 2008 Apr 1;68(7):2391-9
18381447
Acta Neuropathol. 1997 Jun;93(6):551-7
9194893
J Virol. 2010 Apr;84(7):3528-41
20071566
Neuroscience. 1996 Jul;73(2):581-94
8783272
Nat Neurosci. 2005 Feb;8(2):164-72
15665879
Trends Neurosci. 2008 Mar;31(3):146-53
18255164
J Biol Chem. 2005 Jul 1;280(26):24731-7
15860457
Nat Neurosci. 1999 Feb;2(2):115-7
10195193
J Neurosci. 1999 Dec 15;19(24):10948-65
10594076
Arch Neurol. 1984 Mar;41(3):310-20
6320783
Neuron. 2002 Dec 19;36(6):1021-34
12495619
Physiol Rev. 2005 Apr;85(2):523-69
15788705
Clin Microbiol Rev. 2009 Jan;22(1):99-126, Table of Contents
19136436
J Neurochem. 2008 Aug;106(4):1624-36
18540995
Stem Cells Dev. 2009 Mar;18(2):269-82
18651819
Stem Cells. 2006 Sep;24(9):2078-84
16690778
JAMA. 1986 Oct 10;256(14):1904-8
3020264
Nat Genet. 2000 Apr;24(4):372-6
10742100
J Virol. 2005 Aug;79(15):9527-39
16014915
Lab Invest. 2000 Sep;80(9):1373-83
11005206
J Exp Med. 2008 Feb 18;205(2):423-35
18268036
J Neurosci Res. 2002 Sep 15;69(6):837-47
12205677
Development. 2006 May;133(9):1725-34
16571628
Hum Mol Genet. 1998 Aug;7(8):1327-32
9668176
Proc Natl Acad Sci U S A. 1986 Nov;83(21):8361-5
3534887
Neuron. 1997 Aug;19(2):269-81
9292718