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Evolution of virulence in epidemic community-associated methicillin-resistant Staphylococcus aureus
Open accessAbstract
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged worldwide. The United States, in particular, is experiencing a serious epidemic of CA-MRSA that is almost entirely caused by an extraordinarily infectious strain named USA300. However, the molecular determinants underlying the pathogenic success of CA-MRSA are mostly unknown. To gain insight into the evolution of the exceptional potential of USA300 to cause disease, we compared the phylogeny and virulence of USA300 with that of closely related MRSA clones. We discovered that the sublineage from which USA300 evolved is characterized by a phenotype of high virulence that is clearly distinct from other MRSA strains. Namely, USA300 and its progenitor, USA500, had high virulence in animal infection models and the capacity to evade innate host defense mechanisms. Furthermore, our results indicate that increased virulence in the USA300/USA500 sublineage is attributable to differential expression of core genome-encoded virulence determinants, such as phenol-soluble modulins and α-toxin. Notably, the fact that the virulence phenotype of USA300 was already established in its progenitor indicates that acquisition of mobile genetic elements has played a limited role in the evolution of USA300 virulence and points to a possibly different role of those elements. Thus, our results highlight the importance of differential gene expression in the evolution of USA300 virulence. This finding calls for a profound revision of our notion about CA-MRSA pathogenesis at the molecular level and has important implications for design of therapeutics directed against CA-MRSA.
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“which appears to have enhanced virulence as compared to the traditional hospital-associated MRSA strains [26], [27], [28].”
From Interactions of Methicillin Resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in Polymicrobial Wound Infection (2013) · cites this paper as [26]
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Backgroundagr-Dependent Interactions of Staphylococcus aureus USA300 with Human Polymorphonuclear Neutrophils
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“…as USA300 lineage strains of S. aureus are characterized by enhanced production of PSMs relative to other S. aureus clinical strain lineages (Li et al., 2009), our results may partially explain the increased morbidity associated with USA300 strains in patients with osteomyelitis…”
ResultCoagulase‐negative staphylococci as reservoirs of genes facilitating MRSA infection
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“CA-MRSA strains are often more virulent and are capable of causing more severe diseases (14, 15).”
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“Of note, the human CA-MRSA USA300 strain LAC had relatively high levels of expression of SElX which correlates with the previously reported up-regulation of RNAIII and secreted virulence proteins by the USA300 epidemic clone [43].”
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Importance of the Global Regulators Agr and SaeRS in the Pathogenesis of CA-MRSA USA300 Infection
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InfluentialEpistatic Relationships between sarA and agr in Staphylococcus aureus Biofilm Formation
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“showed that the Agr system, which is strongly expressed in CA-MRSA strains and may in part be responsible for high CA-MRSA virulence (Li et al., 2009), inhibits expression of mecA in the CA-MRSA strain USA300 (Memmi et al.”
BackgroundInfluentialSelf-citationStaphylococcal alpha-phenol soluble modulins contribute to neutrophil lysis after phagocytosis
Surewaard, B. G. J., de Haas, C. J. C., Vervoort, F., Rigby, K. M., DeLeo, F. R., Otto, M. J., van Strijp, J. A. G., & Nijland, R. (2013) · Cellular Microbiology · doi:10.1111/cmi.12130 · Cited by 190
“Although the PSM-encoding loci are conserved in the core genome of all sequenced staphylococcal strains, the in vitro expression correlates with the more virulent phenotype between CA-MRSA and HA-MRSA (Wang et al., 2007; Li et al., 2009).”
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“Its dominance has been attributed to a combination of MGEs (8, 28), virulence genes (7), and host and epidemiologic risk factors (2, 14).”
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“aureus phage type 80/81, USA 1100 clone lineage) (5, 15, 17, 19, 28, 31).”
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“However, in accordance with our previous results [21], expression of hla, psma, and RNAIII, was almost exactly the same, and not significantly different, between USA300 and USA500 (Fig.”
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“Furthermore, USA300 strains were more lethal in septic infections compared with archaic and Iberian clones as well as ST239 clones (Brazilian clones) (Li et al., 2009).”
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SaeR Binds a Consensus Sequence within Virulence Gene Promoters to Advance USA300 Pathogenesis
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“common genes between strains [41], we verified the importance”
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Self-citationAntimicrobial resistance in methicillin-resistant staphylococcus aureus
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“USA500 strains are associated with both hospital and community acquired infections (Diep et al., 2006; Klevens et al., 2007; Li et al., 2009).”
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“To assess whether the acetyltransferase activity of SpeG was responsible for conferring polyamine resistance, we employed the antitrypanosomal agent Berenil, which is known to inhibit human spermine/spermidine acetyltransferase (SSAT) activity (Libby and Porter, 1992).”
Staphylococcus aureus: the current state of disease, pathophysiology and strategies for prevention
Dayan, G. H., Mohamed, N., Scully, I. L., Cooper, D., Begier, E. M., Eiden, J., Jansen, K. U., Gurtman, A., & Anderson, A. S. (2016) · Expert Review of Vaccines · doi:10.1080/14760584.2016.1179583 · Cited by 160
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“USA500 [32], and it is tempting to speculate that the South”
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“PSMs are potent toxins, contributing to infection in part by facilitating lysis of multiple host cell types (Wang et al., 2007; Li et al., 2009).”
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“Targets include the PVL gene, the MW1409 and MW0756 loci, and the seh gene for ST1 (USA400) [35, 36]; the PVL gene and the arcA gene (on ACME) for ST8 (USA300) [35–37]; the PVL gene and the etd gene for ST80 [35]; and the PVL gene and the cna and bbp genes for ST30 [38].”
BackgroundInfluentialOrigin, evolution, and global transmission of community-acquired Staphylococcus aureus ST8
Strauß, L., Stegger, M., Akpaka, P. E., Alabi, A. S., Breurec, S., Coombs, G. W., Egyir, B., Larsen, A. R., Laurent, F. J., Monecke, S., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1702472114 · Cited by 146
“S1) share a large resemblance to other studies focusing on the acquisitions of ACME, COMER, and PVL (15, 27).”
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“aureus (MRSA) strains are largely disseminated in clinical settings and infect immunosuppressed hosts while community-associated MRSA strains can cause infections in healthy children and adults [13, 14].”
BackgroundInfluentialPlanet, P. J., LaRussa, S. J., Dana, A. N., Smith, H., Xu, A., Ryan, C., Uhlemann, A., Boundy, S., Goldberg, J., Narechania, A., et al. (2013) · mBio · doi:10.1128/mbio.00889-13 · Cited by 142
“, those encoding phenol soluble modulins and alpha-toxin) likely had a major impact on the virulence of this strain (54, 55).”
BackgroundStaphylococcus aureus Hyaluronidase Is a CodY-Regulated Virulence Factor
Ibberson, C. B., Jones, C. L., Singh, S., Wise, M. C., Hart, M. E., Zurawski, D. V., & Horswill, A. R. (2014) · Infection and Immunity · doi:10.1128/iai.01710-14 · Cited by 133
“Many emerging MRSA isolates are known for causing tissue-destructive infections (5, 6), and it has been proposed that the excessive damage is due, in part, to the large quantities of toxins and secreted enzymes produced by these new isolates (7).”
BackgroundProfiling the surfacome of Staphylococcus aureus
Dreisbach, A., Hempel, K., Buist, G., Hecker, M., Becher, D., & van Dijl, J. M. (2010) · PROTEOMICS · doi:10.1002/pmic.201000062 · Cited by 136
“increased virulence of CA-MRSA are still debated, but this phenotype seems to relate to a differential expression of virulence genes and acquisition of mobile genetic elements [8, 9].”
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“The increased virulence in the USA300/USA500 sublineage was attributed to differential expression of core genome-encoded virulence determinants, such as phenol-soluble modulins and a-toxin [28].”
BackgroundKo, Y.-P., Kuipers, A., Freitag, C. M., Jongerius, I., Medina, E., van Rooijen, W. J. M., Spaan, A. N., van Kessel, K. P. M., Höök, M., & Rooijakkers, S. H. M. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003816 · Cited by 133
“aureus (MRSA) was previously considered as an opportunistic pathogen causing hospital-acquired infections in immune-compromised patients, the emergence of the highly virulent communityassociated MRSA showed that this bacterium could also cause serious infections in otherwise healthy persons [7].”
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Regulatory Adaptation of Staphylococcus aureus during Nasal Colonization of Humans
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“As controls S. aureus strains Newman [49], HG001 formerly named RN1HG [24] and USA300 [50] were used.”
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“Likewise, differences in gene regulation of phenol soluble modulins (psm genes) and alpha toxin (hla) may predate the recent epidemics since these genes are expressed at increased levels in other close relatives, such as USA500 [10, 39, 44].”
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“The decreased expression of rnaIII was even more pronounced in the highly virulent USA300 strain where high agr activity is suspected to be a main contributor to the virulence of the strain [55,56].”
BackgroundWang, F., Fang, R. H., Luk, B. T., Hu, C. J., Thamphiwatana, S., Dehaini, D., Angsantikul, P., Kroll, A. V., Pang, Z., Gao, W., et al. (2016) · Advanced Functional Materials · doi:10.1002/adfm.201505231 · Cited by 122
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“and the Panton-Valentine leukocidin (PVL) [1,2,3].”
BackgroundNygaard, T. K., Pallister, K. B., Dumont, A., DeWald, M., Watkins, R. L., Pallister, E. Q., Malone, C. L., Griffith, S., Horswill, A. R., Torres, V. J., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036532 · Cited by 123
“core genome-encoded virulence elements is largely responsible for the enhanced virulence observed for USA300 [8,9,10].”
BackgroundInactivation of staphylococcal phenol soluble modulins by serum lipoprotein particles
Surewaard, B. G. J., Nijland, R., Spaan, A. N., Kruijtzer, J. A. W., de Haas, C. J. C., & van Strijp, J. A. G. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002606 · Cited by 117
“account for the enhanced virulence, easier spreading and severity of infection of CA-MRSA strains compared to hospital-acquired MRSA strains (HA-MRSA) [6,7].”
BackgroundInfluentialManagement of acute hematogenous osteomyelitis in children
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Life After USA300: The Rise and Fall of a Superbug
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“USA300 has also been shown to exhibit increased expression of α-toxin and phenol-soluble modulins (cytolytic toxins), due to overexpression of the global transcriptional regulators agr and sae [27].”
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“experiments show elevated virulence of this strain compared to contemporary MRSA isolates.(155,156) Notably,”
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Wall teichoic acids mediate increased virulence in Staphylococcus aureus
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“In contrast, LA-MRSA strains exhibit co-resistance to many nonβ-lactam antimicrobials (e.g., antibiotics and metals), including those commonly used in animal production, and many of them belong to CC398 or CC9, as determined by MLST (Bens et al., 2006; Cui and Li, 2009; Neela et al., 2009).”
BackgroundMethicillin-resistant Staphylococcus aureus: an overview for manual therapists
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“The most noticeable feature of the USA300 genome is its rapid diversification and acquisition of different mobile genetic elements, including plasmids (Kennedy et al., 2008; Li et al., 2009).”
BackgroundResistance to leukocytes ties benefits of quorum sensing dysfunctionality to biofilm infection
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“Despite the close genetic similarity between the USA300 and USA500 lineages (21, 26, 30), USA300 has disseminated more widely in the United States.”
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“Recent reports have suggested that the differential expression levels of virulence factors in CAMRSA strains may also contribute to the increased pathogenicity of these strains (19, 20).”
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“The mouse skin infection model is a well-validated model and the histological lesions that result from staphylococcal infection are comparable to human staphylococcal skin infection [3,4,7,8,9].”
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“, 2007), a-toxin (Li et al., 2009) and the PVL leukotoxin (Labandeira-Rey et al.”
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“488 (14) 697 (20) 942 (28) 809 (24) 359 (10) 145 (4) 2004-2007”
Staphylococcus aureus Nuc2 Is a Functional, Surface-Attached Extracellular Nuclease
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“aureus strains [4–6], particularly in community-associated methicillinresistant S.”
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“Interestingly, USA500 strains have been shown to be more virulent than USA300 in a systemic model of murine infection, and to be highly virulent in murine and rabbit skin abscess models (Li et al., 2009; 2010; Alonzo et al., 2012).”
BackgroundResultInfluential
Metadata
- Authors
- Li, M., Diep, B. A., Villaruz, A. E., Braughton, K. R., Jiang, X., DeLeo, F. R., Chambers, H. F., Lu, Y., & Otto, M.
- Affiliations
- National Institutes of Health (US)
- University of California, San Francisco (US)
- Shanghai Medical College of Fudan University (CN)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-04-07
- Volume
- 106
- Issue
- 14
- Pages
- 5883-5888
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2667066
- OpenAlex
- W2005636153
- Cited by
- 394
- References
- 43
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 13 · 2022: 8 · 2021: 10 · 2020: 19 · 2019: 19 · 2018: 17 · 2017: 15 · 2016: 29 · 2015: 31 · 2014: 31 · 2013: 50 · 2012: 34
- FWCI
- 30.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI070289, T32AI060537)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Health Sciences › Medicine › Infectious Diseases › Streptococcal Infections and Treatments
- Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
- Keywords
- community-associated methicillin-resistant Staphylococcus aureus, USA300, virulence evolution, phenol-soluble modulins, alpha-toxin, differential gene expression, mobile genetic elements, animal models of infection
- MeSH terms
- Animals, Disease Outbreaks, Humans, Phylogeny, United States, Virulence, Gene Expression Regulation, Bacterial, Evolution, Molecular, Methicillin-Resistant Staphylococcus aureus
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