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Series GSE40593 Query DataSets for GSE40593
Status Public on Nov 29, 2012
Title Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells
Organism Homo sapiens
Experiment type Expression profiling by array
Summary In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of the TLR3- and UNC-93B-dependent induction of IFN-α/β and/or IFN-λ immunity are prone to HSV-1 encephalitis (HSE) 1-3. The cells responsible for HSE in these children have yet to be identified. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were allowed to differentiate into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-λ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-λ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. The rescue of UNC-93B-deficient cells with the wild-type UNC93B1 allele demonstrated the genetic defect as the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-λ1. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection, a phenotype rescued by wild-type TLR3. Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies
 
Overall design One human ESC line (H9) was differentiated into 4 different cell types, neural rosettes, CNS neurons, astrocytes and immature oligodendrocytes. Rosettes were purified manually, neurons were sorted negatively for the surface markers EGFR and CD44, oligodendrocyte cells were positively sorted for the surface marker O4 while astrocytes were enriched by growth in serum containing medium. All cell types were subjected to RNA extraction and hybridization on Illumina microarrays. Each sample has 3 biological repeats, except rosettes which has 2 repeats. In a seperate experiement, undifferentiated H9 cells along with H9-derived neurons and astrocyes as well as UNC93B-/- iPS derived neurons and astrocytes were also subjected to RNA extraction and hybridization on Illumina microarrays.
 
Contributor(s) Lafaille F, Studer L
Citation(s) 23103873
Submission date Sep 04, 2012
Last update date Feb 18, 2019
Contact name Jeffrey Zhao
Organization name Memorial Sloan Kettering Cancer Center
Department Genomics Core
Street address 1275 York Avenue
City New York
State/province NY
ZIP/Postal code 10065
Country USA
 
Platforms (1)
GPL6884 Illumina HumanWG-6 v3.0 expression beadchip
Samples (18)
GSM997555 H9 hESCs biological rep 1-1
GSM997556 H9 hESCs biological rep 1-2
GSM997557 H9 hESCs biological rep 1-3
Relations
BioProject PRJNA174359

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE40593_RAW.tar 6.3 Mb (http)(custom) TAR
GSE40593_non-normalized.txt.gz 10.5 Mb (ftp)(http) TXT
Raw data is available on Series record
Processed data included within Sample table

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