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Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.

dc.contributor.author Ahn, SH
dc.contributor.author Cowell, LG
dc.contributor.author Deshmukh, H
dc.contributor.author Fowler, Vance Garrison Jr
dc.contributor.author Johnson, N
dc.contributor.author Keum, S
dc.contributor.author Lamlertthon, S
dc.contributor.author Marchuk, DA
dc.contributor.author Nelson, CL
dc.contributor.author Rude, Thomas H
dc.contributor.author Scott, WK
dc.contributor.author Sempowski, Gregory David
dc.contributor.author Sharma-Kuinkel, BK
dc.contributor.author Zaas, Aimee Kirsch
dc.coverage.spatial United States
dc.date.accessioned 2011-06-21T17:32:23Z
dc.date.accessioned 2017-01-01T20:11:06Z
dc.date.issued 2010-09-02
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20824097
dc.identifier.uri https://hdl.handle.net/10161/13319
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.language eng
dc.language.iso en_US
dc.relation.ispartof PLoS Pathog
dc.relation.isversionof 10.1371/journal.ppat.1001088
dc.relation.replaces http://hdl.handle.net/10161/4606
dc.relation.replaces 10161/4606
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
dc.type Journal article
dc.description.version Version of Record
duke.date.pubdate 2010-9-0
duke.description.issue 9
duke.description.volume 6
dc.relation.journal Plos Pathogens
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20824097
pubs.begin-page e1001088
pubs.issue 9
pubs.organisational-group Basic Science Departments
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Clinical Research Institute
pubs.organisational-group Duke Human Vaccine Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Duke Human Vaccine Institute
pubs.organisational-group Medicine, Infectious Diseases
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.publication-status Published online
pubs.volume 6
dc.identifier.eissn 1553-7374


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