Niche-specific genome degradation and convergent evolution shaping Staphylococcus aureus adaptation during severe infections
- University of Melbourne, Australia
- John Hunter Hospital, Australia
- University of Oxford, United Kingdom
Abstract
During severe infections, Staphylococcus aureus moves from its colonising sites to blood and tissues, and is exposed to new selective pressures, thus potentially driving adaptive evolution. Previous studies have shown the key role of the agr locus in S. aureus pathoadaptation, however a more comprehensive characterisation of genetic signatures of bacterial adaptation may enable prediction of clinical outcomes and reveal new targets for treatment and prevention of these infections. Here, we measured adaptation using within-host evolution analysis of 2,590 S. aureus genomes from 396 independent episodes of infection. By capturing a comprehensive repertoire of single-nucleotide and structural genome variations, we found evidence of a distinctive evolutionary pattern within the infecting populations compared to colonising bacteria. These invasive strains had up to 20-fold enrichments for genome degradation signatures and displayed significantly convergent mutations in a distinctive set of genes, linked to antibiotic response and pathogenesis. In addition to agr-mediated adaptation we identified non-canonical, genome-wide significant loci including sucA-sucB and stp1. The prevalence of adaptive changes increased with infection extent, emphasising the clinical significance of these signatures. These findings provide a high-resolution picture of the molecular changes when S. aureus transitions from colonisation to severe infection and may inform correlation of infection outcomes with adaptation signatures.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file 1-6.The code to call, filter and annotated within-host variants and to perform the enrichment analysis is available on github at https://github.com/stefanogg/staph_adaptation_paper
-
Large tandem chromosome duplications facilitate niche adaptation during persistent infection with drug-resistant Staphylococcus aureusPublicly available at NCBI BioProject (accession no. PRJEB9193).
-
Evolution of Multidrug Resistance during Staphylococcus aureus Infection Involves Mutation of the Essential Two Component Regulator WalKRPublicly available at NCBI Sequencing Read Archive (SRA) (accession no. SRA027352).
-
Evolution of Multidrug Resistance during Staphylococcus aureus Infection Involves Mutation of the Essential Two Component Regulator WalKRPublicly available at NCBI BioProject (accession no. PRJNA29567).
-
Evolution of Multidrug Resistance during Staphylococcus aureus Infection Involves Mutation of the Essential Two Component Regulator WalKRPublicly available at NCBI BioProject (accession no. PRJNA29569).
-
Evolutionary dynamics of Staphylococcus aureus during progression from carriage to disease.Publicly available at NCBI BioProject (accession no. PRJEB2862).
-
Within-host evolution of Staphylococcus aureus during asymptomatic carriage.Publicly available at NCBI BioProject (accession no.PRJEB2881).
-
Development of oxacillin resistance in a patient with recurrent Staphylococcus aureus bacteremia.Publicly available at NCBI BioProject (accession no.PRJNA248678).
-
Population Genomics of Reduced Vancomycin Susceptibility in Staphylococcus aureus.Publicly available at NCBI BioProject (accession no.PRJNA259799).
-
Adaptive processes of Staphylococcus aureus isolates during the progression from acute to chronic bone and joint infections in patients.Publicly available at NCBI BioProject (accession no.PRJNA298748).
-
Severe infections emerge from commensal bacteria by adaptive evolution.Publicly available at NCBI BioProject (accession no.PRJEB2862).
-
Emergence and Within-Host Genetic Evolution of Methicillin-Resistant Staphylococcus aureus Resistant to Linezolid in a Cystic Fibrosis Patient.Publicly available at NCBI BioProject (accession no.PRJNA434495).
-
In vivo competition and horizontal gene transfer among distinct Staphylococcus aureus lineages as major drivers for adaptational changes during long-term persistence in humans.Publicly available at NCBI BioProject (accession no.PRJEB22600).
-
Genome Plasticity of agr-Defective Staphylococcus aureus during Clinical Infection.Publicly available at NCBI BioProject (accession no.PRJNA393749).
-
Genomic exploration of sequential clinical isolates reveals a distinctive molecular signature of persistent Staphylococcus aureus bacteraemia.Publicly available at NCBI BioProject (accession no.PRJEB27932).
-
Genomic evolution of Staphylococcus aureus isolates colonizing the nares and progressing to bacteremia.Publicly available at NCBI BioProject (accession no.PRJNA414752).
-
Mutation of Agr Is Associated with the Adaptation of Staphylococcus aureus to the Host during Chronic Osteomyelitis.Publicly available at NCBI BioProject (accession no.PRJNA414566).
-
The Microevolution and Epidemiology of Staphylococcus aureus Colonization during Atopic Eczema Disease Flare.Publicly available at NCBI BioProject (accession no.PRJEB20148).
-
Chronic Staphylococcus aureus Lung Infection Correlates With Proteogenomic and Metabolic Adaptations Leading to an Increased Intracellular Persistence.Publicly available at NCBI BioProject (accession no.PRJNA446073).
-
Staphylococcus aureus Small Colony Variants (SCVs): News From a Chronic Prosthetic Joint Infection.Publicly available at NCBI BioProject (accession no.PRJNA497214).
-
IS256-Mediated Overexpression of the WalKR Two-Component System Regulon Contributes to Reduced Vancomycin Susceptibility in a Staphylococcus aureus Clinical Isolate.Publicly available at NCBI BioProject (accession no.PRJDB8056).
-
Long-Term Intrahost Evolution of Methicillin Resistant Staphylococcus aureus Among Cystic Fibrosis Patients With Respiratory Carriage.Publicly available at NCBI BioProject (accession no.PRJNA527261).
-
Genomic characterization of inpatient evolution of MRSA resistant to daptomycin, vancomycin and ceftaroline.Publicly available at NCBI BioProject (accession no.PRJNA488707).
-
In-Host Evolution of Daptomycin Resistance and Heteroresistance in Methicillin-Resistant Staphylococcus aureus Strains From Three Endocarditis Patients.Publicly available at NCBI BioProject (accession no.PRJNA577181).
-
Distinct Subpopulations of Intravalvular Methicillin-Resistant Staphylococcus aureus with Variable Susceptibility to Daptomycin in Tricuspid Valve Endocarditis.Publicly available at NCBI BioProject (accession no.PRJNA544229).
-
Safety of bacteriophage therapy in severe Staphylococcus aureus infection.Publicly available at NCBI BioProject (accession no.PRJNA541589).
Article and author information
Author details
Abderrahman Hachani
Bernadette C Young
Funding
National Health and Medical Research Council
- Timothy P Stinear
National Health and Medical Research Council
- Benjamin P Howden
The University of Melbourne
- Stefano G Giulieri
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Ethics approval was obtained at each partecipating site to the CAMERA2 trial and written informed onsent was obtained from each participant or surrogate decision maker.
Copyright
© 2022, Giulieri et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,923
- views
-
- 610
- downloads
-
- 31
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Niche-specific genome degradation and convergent evolution shaping Staphylococcus aureus adaptation during severe infections
eLife 11:e77195.
https://doi.org/10.7554/eLife.77195
Further reading
-
- Genetics and Genomics
Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.
-
- Genetics and Genomics
Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.
