title: Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.
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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Ahn
authors.forename: Hitesh
authors.initials: H
authors.lastname: Deshmukh
authors.forename: Nicole
authors.initials: N
authors.lastname: Johnson
authors.forename: Lindsay G
authors.initials: LG
authors.lastname: Cowell
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rude
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Nelson
authors.forename: Aimee K
authors.initials: AK
authors.lastname: Zaas
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.forename: Sehoon
authors.initials: S
authors.lastname: Keum
authors.forename: Supaporn
authors.initials: S
authors.lastname: Lamlertthon
authors.forename: Batu K
authors.initials: BK
authors.lastname: Sharma-Kuinkel
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Sempowski
authors.forename: Vance G
authors.initials: VG
authors.lastname: Fowler
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D018925:Chemokines / Q000378:metabolism; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D013203:Staphylococcal Infections / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000235:genetics* / Q000472:pathogenicity
chemical_list: D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C550729:TNFAIP8 protein, mouse
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