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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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MethodInvasive community-associated MRSA infections: epidemiology and antimicrobial management
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“Others have suggested that prophylactic therapies that target CAMRSA should include inactivated alpha hemolysin (Hla), since Hla is believed to contribute to the severity of USA300 skin infections (12) and is expressed at high levels by USA300 strains (13).”
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BackgroundContribution of YjbIH to Virulence Factor Expression and Host Colonization in Staphylococcus aureus
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Self-citationEpidemiology and Virulence of Community-Associated MRSA
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“The strain is a result of a two step process; first through the acquisition of the SCCmex IV complex which resulted in the clonal type USA500, followed later by the acquisition of several genes including the PVL and ACME loci [24].”
Pichereau, S., Pantrangi, M., Couet, W. R., Badiou, C., Lina, G., Shukla, S. K., & Rose, W. E. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.05113-11 · Cited by 25
“The diversity of virulence factors present in CA-MRSA suggests that cumulative effects of these virulent toxin genes, rather than a single identified locus, contribute to its high pathogenicity (37, 52).”
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“To understand the implications of a greater transmission potential among CA-MRSA strains, the baseline model and above simulations were re-analyzed with βC > βH [11, 12].”
MethodResultKey Role of α-Toxin in Fatal Pneumonia Caused by Staphylococcus aureus Sequence Type 398
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“Moreover, to date, many examples in the literature have reported that Staph. aureus has the trend for increased virulence, especially by MRSA, which may result in more severe and widespread infections (Li et al. 2009).”
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A mouse model of Staphylococcus aureus small intestinal infection
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“aureus strains SF8300 [32] and JH1 [33], as well as the SEBproducing strain RN8098 [21].”
BackgroundUSA300 Staphylococcus aureus persists on multiple body sites following an infection
Read, T. D., Petit, R. A., Yin, Z., Montgomery, T., McNulty, M., & David, M. Z. (2018) · BMC Microbiology · doi:10.1186/s12866-018-1336-z · Cited by 22
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“For sure, this contrasts with highly virulent community-acquired MRSA in which the agr system seems to play a major role in pathogenesis (Li et al., 2009; Pang et al., 2010).”
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“Despite the hypervirulence possessed by strains being to the USA300 clone compared to other MRSA strains [59, 60], 8 of 10 models in this review did not differentiate the clones of MRSA under investigation.”
ResultWu, K., Conly, J. M., McClure-Warnier, J.-A., Kurwa, H. A., & Zhang, K. (2020) · Microorganisms · doi:10.3390/microorganisms8020275 · Cited by 22
“It has been hypothesized that USA300 strains originated from the ancestor strain ST8-MSSA by acquiring SCCmec IV, PVL and ACME [39].”
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“%) were indeed USA300 PFT while 3 strains were identified as USA500.”
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“Less virulent hospital-associated strains characteristically produce smaller amounts of those peptide toxins [6].”
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“Changes in the expression of key genome-encoded toxins such as a-toxin and phenol-soluble modulins (PSMs), were also proposed to have played a role in the evolution of virulence in CA-MRSA strains [32,33,34].”
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“Large-scale genomic datasets have revealed epidemiological consequences of adaptive changes in S. aureus [11,12], and they facilitate identification of key molecular features defining S. aureus traits associated with specific infectious syndromes [13].”
BackgroundMagnesium Links Starvation-Mediated Antibiotic Persistence to ATP
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“aureus strain USA300, the current epidemic strain of communityacquired MRSA infections (Fig 7 and Figure F in S1 File) [31].”
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“aureus isolates, which is consistent with the fact that these strains produce lower levels of δ-toxin in vitro compared to community-acquired strains (28, 55, 56).”
Self-citationLiu, B., & Sun, B. (2020) · Emerging Microbes & Infections · doi:10.1080/22221751.2020.1752116 · Cited by 20
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Cell Heterogeneity in Staphylococcal Communities
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Pediatric Humeral Osteomyelitis
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BackgroundAlsolami, A. A., ALGhasab, N. S., Alharbi, M. S., Bashir, A. I., Saleem, M., Khaja, A. S. S., Aldakheel, D. F., Rakha, E., Alshammari, J. A., Taha, T. E., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13122089 · Cited by 20
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“Like PVL and Hla, PSMs are under strict control of agrA and RNAIII of the agr system (9, 10, 16).”
BackgroundFernandez, J., Hilliard, J. J., Morrow, B. J., Melton, J. L., Flamm, R. K., Barron, A. M., & Lynch, A. S. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00471-11 · Cited by 18
“Community staphylococcal isolates typically express elevated levels of several virulence determinants, which are associated with increased virulence in murine models of bacteremia and skin abscess infection (20).”
BackgroundChen, Y., Yang, J., Wang, Y., You, J., Zhu, W., Liu, C., Luan, Y., Li, L., & Li, H. (2023) · BMC Infectious Diseases · doi:10.1186/s12879-023-08631-z · Cited by 19
“In animal infection models, CA-MRSA strains were significantly more virulent than HA-MRSA [27, 28].”
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“There is some clinical and laboratory evidence that suggests that these community-associated strains of MRSA may be more virulent than classic health care-associated strains.(30) This remains an area of active investigation.”
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Murphy, R. J. T., Ramsay, J. P., Lee, Y. T., Pang, S., O’Dea, M. A., Pearson, J. C., Axon, J. E., Raby, E., Abdulgader, S. M., Whitelaw, A. C., et al. (2019) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2019.08.022 · Cited by 16
“Multilocus sequence type 612 (ST612) is a member of clonal complex 8 (CC8), which includes the dominant USA CA-MRSA, USA300, and the closely related USA500 lineage [4].”
BackgroundChen, P., Chuang, Y., Wang, J., Sheng, W., Chen, Y., & Chang, S. (2021) · Emerging Microbes & Infections · doi:10.1080/22221751.2021.1981158 · Cited by 16
“support increased virulence with USA300 [30].”
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Self-citationGroup 1 CD1-restricted T cells contribute to control of systemic Staphylococcus aureus infection
Visvabharathy, L., Genardi, S., Cao, L., He, Y. Z., Alonzo, F., Berdyshev, E. V., & Wang, C.-R. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008443 · Cited by 16
“hCD1Tg mice expressing CD1b and CD1c molecules (78Tg mice) were infected with MRSA strain USA300 LAC, an isolate that frequently causes communityacquired skin and soft-tissue infections as well as systemic infections [42].”
BackgroundEstrogen and bacterial infection
Hong, L., Liang, H., Man, W., Zhao, Y., & Guo, P. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1556683 · Cited by 15
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“Mice Lacking NKT Cells but Not MAIT Cells Had Increased Bacterial Burden and Neutrophil Infiltration in Infected Liver and Kidneys Following Systemic SA Infection Given that NKT cells have been shown to play a protective role in the early response to many bacterial infections, we sought to determine whether NKT cells…”
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“aureus virulence [23,28].”
A Lesson in Survival: S. aureus versus the Skin
Alonzo, F., & Torres, V. J. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.01.001 · Cited by 15
“Additionally, USA300 isolates have higher activities of gene regulatory systems including the accessory gene regulatory system Agr (Li et al., 2009).”
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“This latter gene cluster is infrequently found in CC8 human clinical isolates (Holtfreter et al. 2007), although it was already described in some of the ‘Archaic’ CC8 clone isolates (Li et al. 2009).”
ResultStevens, C. E., Deventer, A. T., Johnston, P. R., Lowe, P. T., Boraston, A. B., & Hobbs, J. K. (2025) · Molecular Microbiology · doi:10.1111/mmi.70000 · Cited by 12
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“In vitro analyses further supported animal studies in showing that the relative contribution of PVL to MRSA virulence is minor.(1,19,37) Therefore, other virulent factors have been sought.”
BackgroundResultNair, R., Ammann, E. M., Rysavy, M. A., & Schweizer, M. L. (2013) · Infection Control and Hospital Epidemiology · doi:10.1086/674385 · Cited by 14
Guimarães, M. A. A. M., Ramundo, M. S., Américo, M. A., de Mattos, M. C., de Souza, R. R., Ramos‐Junior, E. S., Coelho, L. R., Morrot, A., Melo, P. A., Fracalanzza, S. E. L., et al. (2014) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-014-2253-1 · Cited by 14
“protocol in mice was performed as previously described [23] using Swiss female mice (six weeks old).”
MethodMetabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound
Bruchhagen, C., Jarick, M., Mewis, C., Hertlein, T., Niemann, S., Ohlsen, K., Peters, G., Planz, O., Ludwig, S., & Ehrhardt, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-27445-7 · Cited by 14
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“This may emphasize the utility of a more universally adopted and standardized TNA for the evaluation of vaccines and immunotherapeutics against AT[18,19,25,26].”
BackgroundEshaghi, M., Bibalan, M. H., Pournajaf, A., Gholami, M., & Talebi, M. (2017) · Infectious Diseases in Clinical Practice · doi:10.1097/ipc.0000000000000506 · Cited by 13
“Notably, PSMs are produced in high amounts in the community-associated MRSA USA300/USA500 lineage of the clonal complex 8.(27) Otto et al showed that a novel PSM peptide, PSM-mec, which is encoded on SCCmec determinants, demonstrating the chief toxin gene of S.”
BackgroundFulminant Staphylococcal Infections
Gillet, Y., Henry, T., & Vandenesch, F. (2018) · Microbiology Spectrum · doi:10.1128/microbiolspec.gpp3-0036-2018 · Cited by 13
“An enhanced production of alpha-hemolysin (24, 25) or phenol-soluble modulin (25, 26) and the presence of Arginine Catabolic Mobile Element (ACME), which is strongly associated with USA300 (27), were therefore suspected to be major determinants of severity in SNP, minimizing the potential role of…”
BackgroundOh, J.-Y., Chae, J., Han, J., Song, W., Lee, C., & Park, H. (2020) · Journal of Veterinary Medical Science · doi:10.1292/jvms.19-0523 · Cited by 13
“Since the mid-1990s, MRSA has been known as an important cause of human infections in the general population, which has been mostly designated as community-associated (CA) MRSA [13].”
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High density lipoproteins mediate in vivo protection against staphylococcal phenol-soluble modulins
Hommes, J. W., Kratofil, R. M., Wahlen, S., de Haas, C. J. C., Hildebrand, R. B., Hovingh, G. K., Otto, M., Eck, M. V., Hoekstra, M., Korporaal, S. J. A., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-94651-1 · Cited by 13
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“S. aureus CC5 isolates are prevalent colonizers and agents of infection in the U.S. and have become a predominant IE clonal group (Enright et al., 2002; Tenover et al., 2008; Limbago et al., 2009; Roberts, 2013).”
BackgroundSabat, A. J., Wouthuyzen‐Bakker, M., Rondags, A., Hughes, L., Akkerboom, V., Koutsopetra, O., Friedrich, A. W., & Bathoorn, E. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.964358 · Cited by 13
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“To our knowledge, no study has looked at the host factors involved in USA300 pathogenesis, a hypervirulent isolate compared to other strains [30–32].”
BackgroundUlrich, R. J., Podkowik, M. M., Tierce, R., Irnov, I., Putzel, G., Samhadaneh, N. M., Lacey, K. A., Boff, D., Morales, S. M., Makita, S., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci177872 · Cited by 11
“Often, hypervirulent strains of S . aureus will exhibit differences in growth rates (17), secreted protein production (18), and/or transcriptional profiles (19–21).”
Day, S. R., Moore, C. M., Kundzins, J. R., & Sifri, C. D. (2012) · Virulence · doi:10.4161/viru.22120 · Cited by 12
Microbiome-Independent Effects of Antibiotics in a Murine Model of Nosocomial Infections
Lacey, K. A., González, S. M., Yeung, F., Putzel, G., Podkowik, M. M., Pironti, A., Shopsin, B., Cadwell, K., & Torres, V. J. (2022) · mBio · doi:10.1128/mbio.01240-22 · Cited by 12
Kailasan, S., Kant, R., Noonan-Shueh, M., Kanipakala, T., Liao, G. C., Shulenin, S., Leung, D. W., Alm, R. A., Adhikari, R. P., Amarasinghe, G. K., et al. (2022) · mAbs · doi:10.1080/19420862.2022.2083467 · Cited by 13
Bloomfield, L., Coombs, G. W., Tempone, S., & Armstrong, P. (2020) · Epidemiology and Infection · doi:10.1017/s0950268820000849 · Cited by 12
“The epidemiology of PVL+ USA300 within North America mirrors the WA experience with Queensland CA-MRSA in many ways – a rapid emergence and subsequent dominance of a particular well-adapted clone [1], which is now responsible for an increasing number of healthcare-associated infections [28].”
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“pvl ATCATTAGGTAAAATGT CTGGACATGATCCA GCATCAACTGTATT GGATAGCAAAAGC 433 JCSC2958 (25)”
BackgroundCommunity-Associated Methicillin-ResistantStaphylococcus aureusand Athletes
Małachowa, N., Kobayashi, S. D., & DeLeo, F. R. (2012) · The Physician and Sportsmedicine · doi:10.3810/psm.2012.05.1960 · Cited by 11
“Analysis of agr-regulated virulence gene expression in CA-MRSA strains revealed that high virulence was associated with increased production of virulence molecules in vitro, including the PSMs.(76,77)”
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Pediatric Tibial Osteomyelitis
Stone, B., Street, M., Leigh, W. B., & Crawford, H. (2015) · Journal of Pediatric Orthopaedics · doi:10.1097/bpo.0000000000000472 · Cited by 11
“3 d (2-49) Readmission rate [n/N (%)] 22/76 (29.”
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The rise of antimicrobial resistance: a clear and present danger
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“aureus strains show tremendous variations in gene transcriptional profiles causing diverse pathogenesis, despite sharing a core genome with the similarity of approximately 82% [20, 21].”
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Identification of Staphylococcus aureus Colony-Spreading Stimulatory Factors from Mammalian Serum
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“Community-acquired MRSA (CA-MRSA) has recently become problematic due to its infection of healthy persons [1,2], and is thought to have higher virulence than HA-MRSA.”
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“aureus strains and contribute to the infection’s severity [65,66].”
Background
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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