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1.  Haplotype Association Mapping Identifies a Candidate Gene Region in Mice Infected With Staphylococcus aureus 
G3: Genes|Genomes|Genetics  2012;2(6):693-700.
Exposure to Staphylococcus aureus has a variety of outcomes, from asymptomatic colonization to fatal infection. Strong evidence suggests that host genetics play an important role in susceptibility, but the specific host genetic factors involved are not known. The availability of genome-wide single nucleotide polymorphism (SNP) data for inbred Mus musculus strains means that haplotype association mapping can be used to identify candidate susceptibility genes. We applied haplotype association mapping to Perlegen SNP data and kidney bacterial counts from Staphylococcus aureus-infected mice from 13 inbred strains and detected an associated block on chromosome 7. Strong experimental evidence supports the result: a separate study demonstrated the presence of a susceptibility locus on chromosome 7 using consomic mice. The associated block contains no genes, but lies within the gene cluster of the 26-member extended kallikrein gene family, whose members have well-recognized roles in the generation of antimicrobial peptides and the regulation of inflammation. Efficient mixed-model association (EMMA) testing of all SNPs with two alleles and located within the gene cluster boundaries finds two significant associations: one of the three polymorphisms defining the associated block and one in the gene closest to the block, Klk1b11. In addition, we find that 7 of the 26 kallikrein genes are differentially expressed between susceptible and resistant mice, including the Klk1b11 gene. These genes represent a promising set of candidate genes influencing susceptibility to Staphylococcus aureus.
PMCID: PMC3362298  PMID: 22690378
host genetic susceptibility; infectious disease; kallikrein gene family
2.  Potential Associations between Severity of Infection and the Presence of Virulence-Associated Genes in Clinical Strains of Staphylococcus aureus 
PLoS ONE  2011;6(4):e18673.
The clinical spectrum of Staphylococcus aureus infection ranges from asymptomatic nasal carriage to osteomyelitis, infective endocarditis (IE) and death. In this study, we evaluate potential association between the presence of specific genes in a collection of prospectively characterized S. aureus clinical isolates and clinical outcome.
Methodology/Principal Findings
Two hundred thirty-nine S. aureus isolates (121 methicillin-resistant S. aureus [MRSA] and 118 methicillin-susceptible S. aureus [MSSA]) were screened by array comparative genomic hybridization (aCGH) to identify genes implicated in complicated infections. After adjustment for multiple tests, 226 genes were significantly associated with severity of infection. Of these 226 genes, 185 were not in the SCCmec element. Within the 185 non-SCCmec genes, 171 were less common and 14 more common in the complicated infection group. Among the 41 genes in the SCCmec element, 37 were more common and 4 were less common in the complicated group. A total of 51 of the 2014 sequences evaluated, 14 non-SCCmec and 37 SCCmec, were identified as genes of interest.
Of the 171 genes less common in complicated infections, 152 are of unknown function and may contribute to attenuation of virulence. The 14 non-SCCmec genes more common in complicated infections include bacteriophage-encoded genes such as regulatory factors and autolysins with potential roles in tissue adhesion or biofilm formation.
PMCID: PMC3082525  PMID: 21541311
3.  Two Genes on A/J Chromosome 18 Are Associated with Susceptibility to Staphylococcus aureus Infection by Combined Microarray and QTL Analyses 
PLoS Pathogens  2010;6(9):e1001088.
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.
Author Summary
Staphylococcus aureus has a wide spectrum of human infection, ranging from asymptomatic nasal carriage to overwhelming sepsis and death. Mouse models offer an attractive strategy for investigating complex diseases such as S. aureus infections. A/J mice are highly susceptible to S. aureus infection compared with C57BL/6J mice. We showed that genes on chromosomes 8, 11, and 18 in A/J are responsible for susceptibility to S. aureus by using chromosome substitution strains (CSS). From the ∼4200 genes on these three chromosomes, we identified 191 which were differentially expressed between A/J and C57BL/6J when challenged with S. aureus. Next, we identified two significant QTLs on chromosome 18 that are associated with susceptibility to S. aureus infection in N2 backcross mice. Ten genes (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTLs and were differentially expressed between A/J and C57BL/6J. One gene on each QTL, Tnfaip8 and Seh1l, affected expression of cytokines in mouse macrophages exposed to S. aureus. These cytokine response patterns were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18, but not C57BL/6J. Tnfaip8 and Seh1l are strong candidates for genes influencing susceptibility to S. aureus of A/J mice.
PMCID: PMC2932726  PMID: 20824097
4.  Genotypic Characteristics of Staphylococcus aureus Isolates from a Multinational Trial of Complicated Skin and Skin Structure Infections▿ † 
Journal of Clinical Microbiology  2007;46(2):678-684.
The impact of bacterial genetic characteristics on the outcome of patients with Staphylococcus aureus infections is uncertain. This investigation evaluated potential associations between bacterial genotype and clinical outcome using isolates collected as part of an international phase 2 clinical trial (FAST II) evaluating telavancin for the treatment of complicated skin and skin structure infections (cSSSI). Ninety S. aureus isolates from microbiologically evaluable patients with cSSSI enrolled in the FAST II trial from 11 sites in the United States (56 isolates, or 62%) and 7 sites in South Africa (34 isolates, or 38%) were examined for staphylococcal cassette chromosome mec, agr, and the presence of 31 virulence genes and subjected to pulsed-field gel electrophoresis (PFGE). South African methicillin-susceptible S. aureus (MSSA) isolates were more likely to carry certain virulence genes, including sdrD (P = 0.01), sea (P < 0.01), and pvl (P = 0.01). All 44 (49%) methicillin-resistant S. aureus (MRSA) isolates were from the United States; 37 (84%) were strain USA 300 by PFGE. In the United States, MRSA isolates were more likely than MSSA isolates to carry genes for sdrC (P = 0.03), map/eap (P = 0.05), fnbB (P = 0.11), tst (P = 0.02), sea (P = 0.04), sed (P = 0.04), seg (P = 0.11), sej (P = 0.11), agr (P = 0.09), V8 (P = 0.06), sdrD, sdrE, eta, etb, and see (P < 0.01 for all). MRSA isolates were more often clonal than MSSA isolates by PFGE. Isolates from patients who were cured were significantly more likely to contain the pvl gene than isolates from patients that failed or had indeterminate outcomes (79/84 [94%] versus 3/6 [50%]; P = 0.01). S. aureus strains from different geographic regions have different distributions of virulence genes.
PMCID: PMC2238106  PMID: 18077636

Results 1-4 (4)