Two Genes on A/J Chromosome 18 Are Associated with Susceptibility to Staphylococcus aureus Infection by Combined Microarray and QTL Analyses

PLoS Pathogens

Nicole Johnson¹  Lindsay G. Cowell¹  Sun-Hee Ahn²  Batu K. Sharma-Kuinkel²  Hitesh Deshmukh²  Supaporn Lamlertthon²  Thomas H. Rude²  Aimee K. Zaas²  Vance G. Fowler Jr²  Douglas A. Marchuk³  Sehoon Keum³  William K. Scott⁴  Charlotte L. Nelson⁵  Gregory D. Sempowski⁶ 

[1] Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States of America;Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America;Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America;Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America;Duke Clinical Research Institute, Durham, North Carolina, United States of America;Duke Human Vaccine Institute, Durham, North Carolina, United States of America

关键词: Staphylococcus aureus;    Macrophages;    Cytokines;    Mouse models;    Gene expression;    Neutrophils;    Quantitative trait loci;    Small interfering RNAs;   

DOI  :  10.1371/journal.ppat.1001088

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 N2 backcross mice (F1 [C18A]×C57BL/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 β 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.

【 授权许可】

CC BY