Show simple item record Ahn, SH Deshmukh, H Johnson, N Cowell, LG Rude, TH Scott, WK Nelson, CL Zaas, AK Marchuk, DA Keum, S Lamlertthon, S Sharma-Kuinkel, BK Sempowski, GD Fowler, VG
dc.coverage.spatial United States 2011-06-21T17:32:23Z 2010-09-02
dc.identifier.citation PLoS Pathog, 2010, 6 (9), pp. e1001088 - ?
dc.description.abstract Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N(2) backcross mice (F(1) [C18A]xC57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus-challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 beta and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.
dc.format.extent e1001088 - ?
dc.language ENG
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Pathog
dc.relation.isversionof 10.1371/journal.ppat.1001088
dc.subject Animals
dc.subject Apoptosis Regulatory Proteins
dc.subject Biomarkers
dc.subject Blotting, Western
dc.subject Chemokines
dc.subject Chromosome Mapping
dc.subject Chromosomes, Mammalian
dc.subject Cytokines
dc.subject Enzyme-Linked Immunosorbent Assay
dc.subject Flow Cytometry
dc.subject Gene Expression Profiling
dc.subject Genetic Predisposition to Disease
dc.subject Humans
dc.subject Macrophages, Peritoneal
dc.subject Male
dc.subject Mice
dc.subject Mice, Inbred A
dc.subject Mice, Inbred C57BL
dc.subject Neutrophils
dc.subject Oligonucleotide Array Sequence Analysis
dc.subject Phenotype
dc.subject Polymorphism, Single Nucleotide
dc.subject Quantitative Trait Loci
dc.subject RNA, Messenger
dc.subject RNA, Small Interfering
dc.subject Reverse Transcriptase Polymerase Chain Reaction
dc.subject Sepsis
dc.subject Staphylococcal Infections
dc.subject Staphylococcus aureus
dc.title Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-9-0 en_US
duke.description.endpage e1001088 en_US
duke.description.issue 9 en_US
duke.description.startpage e1001088 en_US
duke.description.volume 6 en_US
dc.relation.journal Plos Pathogens en_US
pubs.issue 9
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Duke Human Vaccine Institute
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Infectious Diseases
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Clinical Research Institute
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Human Vaccine Institute
pubs.publication-status Published online
pubs.volume 6
dc.identifier.eissn 1553-7374

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