Genome Plasticity of
            <i>agr</i>
            -Defective Staphylococcus aureus during Clinical Infection

Altman, Deena R.; Sullivan, Mitchell J.; Chacko, Kieran I.; Balasubramanian, Divya; Pak, Theodore R.; Sause, William E.; Kumar, Krishan; Sebra, Robert; Deikus, Gintaras; Attie, Oliver; Rose, Hannah; Lewis, Martha; Fulmer, Yi; Bashir, Ali Kashif; Kasarskis, Andrew; Schadt, Eric E.; Richardson, Anthony R.; Torres, Victor J.; Shopsin, Bo; Bakel, Harm van

doi:10.1128/iai.00331-18

Cited by 55 publications

(46 citation statements)

References 93 publications

(109 reference statements)

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“…Inversions were much more frequent in CC5 and USA100, which may reflect higher similarity between endogenous prophages and/or the increased divergence between isolates in the USA100 lineage. Most inversions could only be resolved by long-read sequencing data, and our results, combined with our previous observations among MSSA isolates (Altman et al 2018) , suggest that prophage-mediated recombinations may be more frequent than previously appreciated. Indeed, one inversion event occurred in the outbreak clone during the spread from the adult wards to the NICU.…”

Section: Discussionsupporting

confidence: 70%

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Complete genome screening of clinical MRSA isolates identifies lineage diversity and provides full resolution of transmission and outbreak events

et al. 2019

Preprint

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Whole-genome sequencing (WGS) of Staphylococcus aureus is increasingly used as part of infection prevention practices, but most applications are focused on conserved core genomic regions due to limitations of short-read technologies. In this study we established a long-read technology-based WGS screening program of all first-episode MRSA blood infections at a major urban hospital. A survey of 132 MRSA genomes assembled from long reads revealed widespread gain/loss of accessory mobile genetic elements among established hospital-and community-associated lineages impacting >10% of each genome, and frequent megabase-scale inversions between endogenous prophages. We also characterized an outbreak of a CC5/ST105/USA100 clone among 3 adults and 18 infants in a neonatal intensive care unit (NICU) lasting 7 months. The pattern of changes among complete outbreak genomes provided full spatiotemporal resolution of its origins and progression, which was characterized by multiple sub-transmissions and likely precipitated by equipment sharing. Compared to other hospital strains, the outbreak strain carried distinct mutations and accessory genetic elements that impacted genes with roles in metabolism, resistance and persistence. This included a DNA-recognition domain recombination in the hsdS gene of a Type-I restriction-modification system that altered DNA methylation. RNA-Seq profiling showed that the (epi)genetic changes in the outbreak clone attenuated agr gene expression and upregulated genes involved in stress response and biofilm formation. Overall our findings demonstrate that long-read sequencing substantially improves our ability to characterize accessory genomic elements that impact MRSA virulence and persistence, and provides valuable information for infection control efforts.

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Section: Discussionsupporting

confidence: 70%

“…PacBio SMRT sequencing data were assembled using a custom genome assembly and finishing pipeline (Altman et al 2018) . Briefly, sequencing data was first assembled with HGAP3 version 2 · 2 · 0 (Chin et al 2013) .…”

Section: Complete Genome Assembly and Finishingmentioning

confidence: 99%

Complete genome screening of clinical MRSA isolates identifies lineage diversity and provides full resolution of transmission and outbreak events

et al. 2019

Preprint

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“…We prepared sequencing libraries from DNA extracted from each MRSA isolate as previously described (24,96). Whole-genome sequencing was performed using Illumina HiSeq 2000 with 100-base paired-end reads or a PacBio RSII instrument (24,49,96). Paired-end Illumina reads were mapped against USA300_FPR3757 reference genome using Burrows-Wheeler Aligner (BWA) (97).…”

Section: Discussionmentioning

confidence: 99%

Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus

Copin

Sause

Fulmer

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The past two decades have witnessed an alarming expansion of staphylococcal disease caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The factors underlying the epidemic expansion of CA-MRSA lineages such as USA300, the predominant CA-MRSA clone in the United States, are largely unknown. Previously described virulence and antimicrobial resistance genes that promote the dissemination of CA-MRSA are carried by mobile genetic elements, including phages and plasmids. Here, we used high-resolution genomics and experimental infections to characterize the evolution of a USA300 variant plaguing a patient population at increased risk of infection to understand the mechanisms underlying the emergence of genetic elements that facilitate clonal spread of the pathogen. Genetic analyses provided conclusive evidence that fitness (manifest as emergence of a dominant clone) changed coincidently with the stepwise emergence of (i) a unique prophage and mutation of the regulator of the pyrimidine nucleotide biosynthetic operon that promoted abscess formation and colonization, respectively, thereby priming the clone for success; and (ii) a unique plasmid that conferred resistance to two topical microbiocides, mupirocin and chlorhexidine, frequently used for decolonization and infection prevention. The resistance plasmid evolved through successive incorporation of DNA elements from non-S. aureus spp. into an indigenous cryptic plasmid, suggesting a mechanism for interspecies genetic exchange that promotes antimicrobial resistance. Collectively, the data suggest that clonal spread in a vulnerable population resulted from extensive clinical intervention and intense selection pressure toward a pathogen lifestyle that involved the evolution of consequential mutations and mobile genetic elements.

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“…Altman and coworkers have shown that within-host loss of agr function was associated with increased genetic divergence between distinct S. aureus subclones 44 . In synthesis, whereas agr dysfunction is adaptive for survival in the infected bone, it may be counter adaptive outside such niche.…”

Section: Discussionmentioning

confidence: 99%

“…In the present report we show that S. aureus can regain CP production when subjected to selection pressure in vivo through a mechanism that does not require RNAIII expression. Indeed, in a previous study it has been shown that genetic changes occurring in an agr-defective infecting S. aureus strain resulted in increased virulence in a murine model of bloodstream infection thus bypassing the agr mutation 44 . The S. aureus derivative obtained after passage through the bloodstream displayed a significant reduction in the capacity to trigger TNFα production and became less adapted to bone as ascertained by its decreased capacity to induce osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

Acapsular Staphylococcus aureus with a non-functional agr regains capsule expression after passage through the bloodstream in a bacteremia mouse model

Suligoy

Díaz

Gehrke

et al. 2020

Sci Rep

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Selection pressures exerted on Staphylococcus aureus by host factors during infection may lead to the emergence of regulatory phenotypes better adapted to the infection site. traits convenient for persistence may be fixed by mutation thus turning these mutants into microevolution endpoints. The feasibility that stable, non-encapsulated S. aureus mutants can regain expression of key virulence factors for survival in the bloodstream was investigated. S. aureus agr mutant HU-14 (IS256 insertion in agrC) from a patient with chronic osteomyelitis was passed through the bloodstream using a bacteriemia mouse model and derivative P3.1 was obtained. Although IS256 remained inserted in agrC, P3.1 regained production of capsular polysaccharide type 5 (CP5) and staphyloxanthin. Furthermore, P3.1 expressed higher levels of asp23/SigB when compared with parental strain HU-14. Strain P3.1 displayed decreased osteoclastogenesis capacity, thus indicating decreased adaptability to bone compared with strain HU-14 and exhibited a trend to be more virulent than parental strain HU-14. Strain P3.1 exhibited the loss of one IS256 copy, which was originally located in the HU-14 noncoding region between dnaG (DNA primase) and rpoD (sigA). this loss may be associated with the observed phenotype change but the mechanism remains unknown. in conclusion, S. aureus organisms that escape the infected bone may recover the expression of key virulence factors through a rapid microevolution pathway involving SigB regulation of key virulence factors. Staphylococcus aureus is a transient, sometimes permanent member of the human microbiota in the nares and skin of a significant number of healthy individuals. As predisposing conditions emerge in the host, this opportunistic species may cause infections with different severity, ranging from mild skin and soft tissue infection to severe disseminated disease 1,2. Treatment of S. aureus infections is hampered by widespread dissemination of methicillin-resistant S. aureus (MRSA) 3 and by the frequent emergence of S. aureus with low level resistance to vancomycin 4. Whereas MRSA was primarily considered a nosocomial pathogen 5 , it is now unanimously accepted that MRSA also affects individuals of the general community with no previous exposure to health care settings 6,7. Up to 1.5-2% of patients receiving an orthopedic prosthetic device becomes infected and a significant number of these infections are caused by S. aureus. Most osteomyelitis caused by S. aureus become refractory to antibiotic treatment soon after bacteria settles on the prosthetic device surface and in bone tissue 1 .

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Genome Plasticity of agr -Defective Staphylococcus aureus during Clinical Infection

Cited by 55 publications

References 93 publications

Complete genome screening of clinical MRSA isolates identifies lineage diversity and provides full resolution of transmission and outbreak events

Complete genome screening of clinical MRSA isolates identifies lineage diversity and provides full resolution of transmission and outbreak events

Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus

Acapsular Staphylococcus aureus with a non-functional agr regains capsule expression after passage through the bloodstream in a bacteremia mouse model

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