Dataset Information

Sustained Circulating Bacterial Deoxyribonucleic Acid Is Associated With Complicated Staphylococcus aureus Bacteremia.

ABSTRACT:

Background

Staphylococcus aureus (SA) bacteremia often requires a long treatment duration with antibiotics to prevent relapse due to the ability of SA to establish reservoirs of infection in sites such as heart and bone. These metastatic sites of infection cannot be serially sampled to monitor the clearance of SA infection. This study aimed to establish a link between persistence of circulating SA deoxyribonucleic acid (SA-DNA) and tissue reservoirs in patients with SA bacteremia.

Methods

A highly sensitive quantitative polymerase chain reaction was used to measure whole blood SA-DNA and plasma-derived SA cell-free DNA (SA-cfDNA) in a set of longitudinal samples from 73 patients with confirmed SA bacteremia and correlated with clinical features.

Results

Blood SA-DNA was detected for longer than the duration of positive blood cultures. Longer duration of circulating bacterial DNA was observed in complicated SA bacteremia infections, such as endocarditis and osteoarticular infections, compared with uncomplicated bloodstream infections. In contrast, traditional blood cultures demonstrated similar time to clearance regardless of foci of infection. Plasma-derived SA-cfDNA showed concordance with blood SA-DNA levels. Baseline levels of SA-DNA were higher in patients presenting with greater clinical severity and complicated bacteremia.

Conclusions

Prolonged levels of circulating SA-DNA in patients with complicated tissue reservoirs after clearance of blood cultures observed in this single-center study should be validated in additional cohorts to assess the potential utility for monitoring clearance of infection in patients with SA bacteremia.

SUBMITTER: Gutierrez J

PROVIDER: S-EPMC6475589 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Sustained Circulating Bacterial Deoxyribonucleic Acid Is Associated With Complicated <i>Staphylococcus aureus</i> Bacteremia.

Gutierrez Johnny J Guimaraes Alessander O AO Lewin-Koh Nicholas N Berhanu Aklile A Xu Min M Cao Yi Y Kim Janice J Yan Donghong D Chang Joanna K JK Dinoso Jason B JB Koss Catherine A CA Clemenzi-Allen Angelo A Chambers Henry F HF Peck Melicent C MC Baruch Amos A Rosenberger Carrie M CM

Open forum infectious diseases 20190226 4

<h4>Background</h4><i>Staphylococcus aureus</i> (SA) bacteremia often requires a long treatment duration with antibiotics to prevent relapse due to the ability of SA to establish reservoirs of infection in sites such as heart and bone. These metastatic sites of infection cannot be serially sampled to monitor the clearance of SA infection. This study aimed to establish a link between persistence of circulating SA deoxyribonucleic acid (SA-DNA) and tissue reservoirs in patients with SA bacteremia. ...[more]

PMID: 31024970

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Project description:Abstract Background SAB is a serious, common infection. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery set of patients, and then evaluated the nominally significant genes in a replication set of patients using custom-capture sequencing. Methods The discovery set comprised 84 complicated SAB cases (endocarditis or bone/joint infection) frequency-matched by age (in deciles), sex, and bacterial clonal complex (CC5/30, CC8) to 84 uncomplicated SAB controls. All were white inpatients at Duke University. WES utilized Agilent SureSelect 72Mb capture kits, followed by sequencing on an Illumina HiSeq2000, alignment and base calling with a standard pipeline. The SKAT-O and EPACTS packages were used for gene-based association tests and logistic regression models with Firth bias correction, respectively. Both controlled for age, sex, and clonal complex as covariates. The replication set of 122 complicated SAB cases and 118 uncomplicated SAB controls was frequency matched by age, sex, and clonal complex. All were white Europeans collected by the Statens Serum Institute. An Agilent SureSelect 2Mb capture array captured genic sequence for 342 genes nominally associated with complicated SAB in discovery (SKAT-O P < 0.035). Sequencing and data analysis proceeded as for WES. A Bonferroni-corrected gene-based test P-value of 1.5×10–4 determined significance in the replication set. Results One gene, GLS2, was significantly associated with complicated SAB in the replication set (P = 1.2 x 10–4). The strongest single-variant association in all 342 genes was rs2657878 in GLS2 (p = 5×10−4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4x10-3) in which the minor allele (associated here with complicated SAB) has previously been shown to reduce circulating glutamine levels. Conclusion Comprehensive examination of the coding sequence for association with complicated SAB in a two-stage discovery/replication design identified a novel candidate gene. GLS2 is an interesting candidate for complicated SAB due to its role in regulating glutamine production, a key factor in activation of T-cell production. Disclosures V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, Basilea, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Research grant; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: author on several chapters, Royalties

Project description:The role of host genetic variation in the development of complicated Staphylococcus aureus bacteremia (SAB) is poorly understood. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 complicated and 84 uncomplicated, frequency matched by age, sex, and bacterial clonal complex [CC]), and then evaluated the most significantly associated genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched for age, sex, and CC) using targeted sequence capture. In the discovery sample, gene-based analysis using the SKAT-O program identified 334 genes associated with complicated SAB at p<3.5 x 10-3. These, along with eight biologically relevant candidate genes were examined in the replication sample. Gene-based analysis of the 342 genes in the replication sample using SKAT-O identified one gene, GLS2, significantly associated with complicated SAB (p = 1.2 x 10-4) after Bonferroni correction. In Firth-bias corrected logistic regression analysis of individual variants, the strongest association across all 10,931 variants in the replication sample was with rs2657878 in GLS2 (p = 5 x 10-4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4 x 10-3) in which the minor allele (associated here with complicated SAB) has been previously associated with lower plasma concentration of glutamine. In a microarray-based gene-expression analysis, individuals with SAB exhibited significantly lower expression levels of GLS2 than healthy controls. Similarly, Gls2 expression is lower in response to S. aureus exposure in mouse RAW 264.7 macrophage cells. Compared to wild-type cells, RAW 264.7 cells with Gls2 silenced by CRISPR-Cas9 genome editing have decreased IL1-β transcription and increased nitric oxide production after S. aureus exposure. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in leukocyte activation.

Dataset Information

Sustained Circulating Bacterial Deoxyribonucleic Acid Is Associated With Complicated Staphylococcus aureus Bacteremia.

Background

Methods

Results

Conclusions

Publications

Sustained Circulating Bacterial Deoxyribonucleic Acid Is Associated With Complicated <i>Staphylococcus aureus</i> Bacteremia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Sustained Circulating Bacterial Deoxyribonucleic Acid Is Associated With Complicated Staphylococcus aureus Bacteremia.

Background

Methods

Results

Conclusions

Publications

Sustained Circulating Bacterial Deoxyribonucleic Acid Is Associated With Complicated &lt;i&gt;Staphylococcus aureus&lt;/i&gt; Bacteremia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Sustained Circulating Bacterial Deoxyribonucleic Acid Is Associated With Complicated <i>Staphylococcus aureus</i> Bacteremia.