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
-
- 2,865
- views
-
- 604
- downloads
-
- 30
- 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
- Microbiology and Infectious Disease
The ability to analyze the function of all genes in a genome is highly desirable, yet challenging in Leishmania due to a repetitive genome, limited DNA repair mechanisms, and lack of RNA interference in most species. While our introduction of a cytosine base editor (CBE) demonstrated potential to overcome these limitations (Engstler and Beneke, 2023), challenges remained, including low transfection efficiency, variable editing rates across species, parasite growth effects, and competition between deleterious and non-deleterious mutations. Here, we present an optimized approach addressing these issues. We identified a T7 RNAP promoter variant ensuring high editing rates across Leishmania species without compromising growth. A revised CBE single-guide RNAs (sgRNAs) scoring system was developed to prioritize STOP codon generation. Additionally, a triple-expression construct was created for stable integration of CBE sgRNA expression cassettes into a Leishmania safe harbor locus using AsCas12a ultra-mediated DNA double-strand breaks, increasing transfection efficiency by ~400-fold to 1 transfectant per 70 transfected cells. Using this improved system for a small-scale proof-of-principle pooled screen, we successfully confirmed the essential and fitness-associated functions of CK1.2, CRK2, CRK3, AUK1/AIRK, TOR1, IFT88, IFT139, IFT140, and RAB5A in Leishmania mexicana, demonstrating a significant improvement over our previous method. Lastly, we show the utility of co-expressing AsCas12a ultra, T7 RNAP, and CBE for hybrid CRISPR gene replacement and base editing within the same cell line. Overall, these improvements will broaden the range of possible gene editing applications in Leishmania species and will enable a variety of loss-of-function screens in the near future.
-
- Genetics and Genomics
- Neuroscience
Spinal muscular atrophy (SMA) is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. While traditionally viewed as a motor neuron disorder, there is involvement of various peripheral organs in SMA. Notably, fatty liver has been observed in SMA mouse models and SMA patients. Nevertheless, it remains unclear whether intrinsic depletion of SMN protein in the liver contributes to pathology in the peripheral or central nervous systems. To address this, we developed a mouse model with a liver-specific depletion of SMN by utilizing an Alb-Cre transgene together with one Smn2B allele and one Smn1 exon 7 allele flanked by loxP sites. Initially, we evaluated phenotypic changes in these mice at postnatal day 19 (P19), when the severe model of SMA, the Smn2B/- mice, exhibit many symptoms of the disease. The liver-specific SMN depletion does not induce motor neuron death, neuromuscular pathology or muscle atrophy, characteristics typically observed in the Smn2B/- mouse at P19. However, mild liver steatosis was observed, although no changes in liver function were detected. Notably, pancreatic alterations resembled that of Smn2B/-mice, with a decrease in insulin-producing β-cells and an increase in glucagon-producingα-cells, accompanied by a reduction in blood glucose and an increase in plasma glucagon and glucagon-like peptide (GLP-1). These changes were transient, as mice at P60 exhibited recovery of liver and pancreatic function. While the mosaic pattern of the Cre-mediated excision precludes definitive conclusions regarding the contribution of liver-specific SMN depletion to overall tissue pathology, our findings highlight an intricate connection between liver function and pancreatic abnormalities in SMA.
