Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.
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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.
Apoptosis Regulatory Proteins
Enzyme-Linked Immunosorbent Assay
Gene Expression Profiling
Genetic Predisposition to Disease
Mice, Inbred A
Mice, Inbred C57BL
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Quantitative Trait Loci
RNA, Small Interfering
Reverse Transcriptase Polymerase Chain Reaction
Published Version (Please cite this version)10.1371/journal.ppat.1001088
Publication InfoAhn, Sun-Hee; Deshmukh, Hitesh; Johnson, Nicole; Cowell, Lindsay G; Rude, Thomas H; Scott, William K; ... Fowler, Vance G (2010). Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses. PLoS Pathog, 6(9). pp. e1001088. 10.1371/journal.ppat.1001088. Retrieved from https://hdl.handle.net/10161/13319.
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Florence McAlister Distinguished Professor of Medicine
Determinants of Outcome in Patients with Staphylococcus aureus Bacteremia Antibacterial ResistancePathogenesis of Bacterial Infections Tropical medicine/International Health
Professor of Molecular Genetics and Microbiology
Vascular Morphogenesis: A Human Genetics Approach Advances in our understanding of fundamental biological events can often be made by the analysis of defects manifested in inherited diseases. The genes responsible for these genetic syndromes often encode proteins that act at critical points of the pathways that control fundamental biological processes such as cell division, differentiation, and cell death. This approach has lead to the discovery of novel gene products and/or biochem
Professor in Medicine
Dr. Sempowski earned his PhD in Immunology from the University of Rochester and was specifically trained in the areas of inflammation, wound healing, and host response (innate and adaptive). Dr. Sempowski contributed substantially to the field of lung inflammation and fibrosis defining the roles of pulmonary fibroblast heterogeneity and CD40/CD40L signaling in regulating normal and pathogenic lung inflammation. During his postdoctoral training with Dr. Barton F. H
Professor of Medicine
Medical education Genomic applications for diagnosis of infectious diseases Genomic applications for prediction of infectious diseases
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