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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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BackgroundContribution of Staphylococcal Enterotoxin B toStaphylococcus aureusSystemic Infection
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“aureus strain USA300_FPR3757 by a few singlenucleotide polymorphisms (39).”
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BackgroundCD4+ T Cells Promote the Pathogenesis of Staphylococcus aureus Pneumonia
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Staphylococcus aureus , Antibiotic Resistance, and the Interaction with Human Neutrophils
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“CA-MRSA usually has a particular epidemiology, the most successful lineage being USA300 [1].”
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BackgroundLooking toward basic science for potential drug discovery targets against community‐associated MRSA
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“MRSA and CA-MRSA presents a significant threat to public health and are difficult to manage (14).”
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“Briefly, AgrD is the precursor peptide of AIP, AgrB is a membrane protease involved in generating AIP, AgrC is a histidine kinase that is activated by binding AIP, and AgrA is a response regulator that induces transcription of RNAII and RNAIII through the P2 and P3 promoters, respectively.”
BackgroundInfluentialMethicillin-resistant Staphylococcus aureus antibiotic resistance and virulence
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“The terrible spread of CA-MRSA is thought to be associated with strengthened virulence and increased transmissibility compared to former HA-MRSA.”
InfluentialBowers, J. R., Driebe, E. M., Albrecht, V. S., McDougal, L. K., Granade, M. E., Roe, C. C., Lemmer, D., Rasheed, J. K., Engelthaler, D. M., Keim, P., et al. (2018) · mSphere · doi:10.1128/msphere.00464-17 · Cited by 47
“[7] and used in the CDC’s quality management system protocols), NRS385 (15) and ATCC BAA-1763 (two publicly available isolates typed as USA500), and the genomes of COL (an Archaic isolate from 1960 [11]), HPV107 and E2125 (ST247 Iberian strains from the 1960s [54, 55]), and NCTC 8325 (a laboratory strain originally is…”
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“The enhanced virulence phenotype of USA300 is largely attributable to the relatively high expression of virulence factors, such as a-toxin and phenol soluble modulins [6].”
BackgroundMorrison, J. M., Miller, E. W., Benson, M. A., Alonzo, F., Yoong, P., Torres, V. J., Hinrichs, S. H., & Dunman, P. M. (2012) · Journal of Bacteriology · doi:10.1128/jb.06708-11 · Cited by 50
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“…as the predominant cause of community-acquired cutaneous infections in the United States (Uhlemann et al., 2014), and these isolates show enhanced virulence factor expression and virulence relative to those from the USA200 lineage (Li et al., 2009; Cheung et al., 2011; Uhlemann et al., 2014).”
BackgroundZapf, R. L., Wiemels, R. E., Keogh, R. A., Holzschu, D. L., Howell, K. M., Trzeciak, E. R., Caillet, A. R., King, K. A., Selhorst, S., Naldrett, M. J., et al. (2019) · mBio · doi:10.1128/mbio.02484-18 · Cited by 44
Junio, H. A., Todd, D. A., Ettefagh, K. A., Ehrmann, B. M., Kavanaugh, J. S., Horswill, A. R., & Cech, N. B. (2013) · Journal of Chromatography B · doi:10.1016/j.jchromb.2013.04.019 · Cited by 42
Crisp, J. G., Takhar, S. S., Moran, G. J., Krishnadasan, A., Dowd, S. E., Finegold, S. M., Summanen, P. H., Talan, D. A., for the EMERGEncy ID Net Study Group, Abrahamian, F. M., et al. (2015) · Clinical Infectious Diseases · doi:10.1093/cid/civ655 · Cited by 42
Moran, J. C., Alorabi, J. A., & Horsburgh, M. J. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00033 · Cited by 43
Li, J., Wang, L., Ip, M., Sun, M., Sun, J., Huang, G., Wang, C., Deng, L., Zheng, Y., Fu, Z., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070602 · Cited by 43
“The isolates were screened for 42 known virulence genes by PCRs using conserved primers as previously described and listed in Table S1 in file S1[32–39].”
MethodGraves, S. F., Kobayashi, S. D., Braughton, K. R., Diep, B. A., Chambers, H. F. “., Otto, M. J., & DeLeo, F. R. (2010) · Microbes and Infection · doi:10.1016/j.micinf.2010.02.005 · Cited by 43
“Experimental data with animal infection models using CA-MRSA strains provides strong support to this notion [3,4].”
BackgroundSelf-citationNickerson, N. N., Ip, J., Passos, D. T., & Mcgavin, M. J. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06974.x · Cited by 45
“However, strains belonging to the CC30 clonal complex (Table 1) cleared the elastin, including: (i) WBG10049, which was highly active and corresponds to a hypervirulent community-acquired MRSA (Robinson et al., 2005), (ii) BK12003, a closely related but methicillin susceptible clinical isolate, (iii) M1015, which is a…”
InfluentialHota, B. N., Lyles, R. D., Rim, J., Popovich, K. J., Rice, T., Aroutcheva, A. A., & Weinstein, R. A. (2011) · Clinical Infectious Diseases · doi:10.1093/cid/cir472 · Cited by 41
“Additional toxins have been found in community-associated MRSA strains USA300 and -400 that may also mediate illness severity [38].”
BackgroundCurcumin attenuates staphylococcus aureus‐induced acute lung injury
Xu, F., Diao, R., Liu, J., Kang, Y., Wang, X., & Shi, L. (2014) · The Clinical Respiratory Journal · doi:10.1111/crj.12113 · Cited by 42
“aureus replicates at the site of infection and produces surface proteins such as adhesins, protein A and secreted exoproteins, including toxins, hemolysins, and tissue-degrading enzymes (23, 24).”
BackgroundSchwartz, K., Sekedat, M. D., Syed, A. K., O’Hara, B. J., Payne, D. E., Lamb, A. M., & Boles, B. R. (2014) · Infection and Immunity · doi:10.1128/iai.02111-14 · Cited by 43
“For this work, we utilized the community-associated (CA)-MRSA USA300 strain LAC, which exhibits robust Agr activity producing high levels of PSMs (12, 43).”
BackgroundMethodBumah, V. V., Whelan, H. T., Masson‐Meyers, D. S., Quirk, B. J., Buchmann, E. V., & Enwemeka, C. S. (2015) · Lasers in Medical Science · doi:10.1007/s10103-015-1722-9 · Cited by 40
“Clinical cases of CA-MRSA have increased, while the proportion of patients with hospital associated MRSA (HAMRSA) has decreased [38–40].”
BackgroundTomlinson, B. R., Malof, M. E., & Shaw, L. N. (2021) · Microbial Genomics · doi:10.1099/mgen.0.000598 · Cited by 42
“USA500 is the suspected progenitor of USA300 [29, 42], therefore, the USA300 reference genome was used.”
Mendes, R. E., Farrell, D. J., Sader, H. S., Flamm, R. K., & Jones, R. N. (2014) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dku421 · Cited by 39
Chen, C., Huang, Y., Su, L., Wu, T., Huang, S.-H., Chien, C., Chen, P.-Y., Lu, M., & Ko, W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101184 · Cited by 39
“Current evidence suggested that community strains with or without PVL genes were more virulent than the global pandemic, nosocomial MRSA strains, although the greater virulence appeared to be confined to skin and soft tissue infections in clinical studies or experimental animal models [9,33,34].”
BackgroundLysin Therapy for Staphylococcus aureus and Other Bacterial Pathogens
Fischetti, V. A. (2015) · Current topics in microbiology and immunology · doi:10.1007/82_2015_5005 · Cited by 39
The Iron-Repressed, AraC-Like Regulator MpeR Activates Expression of fetA in Neisseria gonorrhoeae
Hollander, A. M., Mercante, A. D., Shafer, W. M., & Cornelissen, C. N. (2011) · Infection and Immunity · doi:10.1128/iai.05806-11 · Cited by 38
“(40) that global regulators of virulence genes are responsible for variable virulence among strains.”
BackgroundPan-genomic perspective on the evolution of the Staphylococcus aureus USA300 epidemic
Jamrozy, D. M., Harris, S. R., Mohamed, N., Peacock, S. J., Tan, C. Y., Parkhill, J., Anderson, A. S., & Holden, M. T. G. (2016) · Microbial Genomics · doi:10.1099/mgen.0.000058 · Cited by 37
“The contribution of MGEs to the success of USA300 has been a subject of debate and generation of the hypothesis that the accessory genome has promoted the enhanced transmission of USA300 (Li et al., 2009).”
BackgroundResultInfluentialFrisch, M. B., Castillo‐Ramírez, S., Petit, R. A., Farley, M. M., Ray, S. M., Albrecht, V. S., Limbago, B. M., Hernandez, J., See, I., Satola, S. W., et al. (2018) · mSphere · doi:10.1128/msphere.00571-17 · Cited by 37
“This clade contained the BD02-25 strain originally used as the USA500 reference isolate (12).”
MethodThe 5′ NAD Cap of RNAIII Modulates Toxin Production in Staphylococcus aureus Isolates
Morales-Filloy, H. G., Zhang, Y., Nübel, G., George, S. E., Korn, N., Wolz, C., & Jäschke, A. (2019) · Journal of Bacteriology · doi:10.1128/jb.00591-19 · Cited by 37
Yao, X., Chen, T., Shen, X., Zhao, Y., Wang, M., Rao, X., Yin, S., Wang, J., Gong, Y., Lu, S., et al. (2015) · Molecular Microbiology · doi:10.1111/mmi.13116 · Cited by 37
“Increases in infection frequency and severity are often associated with the emergence of distinct bacterial clones of high virulence (Musser, 1996; Li et al., 2009).”
BackgroundSelf-citationBerlon, N. R., Qi, R., Sharma‐Kuinkel, B. K., Joo, H., Park, L. P., George, D., Thaden, J. T., Messina, J. A., Maskarinec, S. A., Mueller‐Premru, M., et al. (2015) · Journal of Infection · doi:10.1016/j.jinf.2015.06.005 · Cited by 36
Self-citationCurrent status of Staphylococcus aureus infection in a central teaching hospital in Shanghai, China
Li, T., Song, Y. J., Zhu, Y., Du, X., & Li, M. (2013) · BMC Microbiology · doi:10.1186/1471-2180-13-153 · Cited by 35
“aureus [11], indicating that discrete sequence types (STs) may correlate with specific infection types.”
BackgroundSelf-citationChen, Y., Yeh, A. J., Cheung, G. Y. C., Villaruz, A. E., Tan, V. Y., Joo, H., Chatterjee, S. S., Yu, Y., & Otto, M. J. (2014) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiu462 · Cited by 35
“Another hypothesis explains the increased virulence of CA- as opposed to HAMRSA strains by increased expression of core genome-encoded toxin genes, such as mainly phenol-soluble modulins (PSMs) and α-toxin [17–19].”
BackgroundSelf-citationStaphylococcus aureus in Inflammation and Pain: Update on Pathologic Mechanisms
Rasquel-Oliveira, F. S., Ribeiro, J. M., Martelossi-Cebinelli, G., Costa, F., Nakazato, G., Casagrande, R., & Verri, W. A., Jr. (2025) · Pathogens · doi:10.3390/pathogens14020185 · Cited by 41
AraC-Type Regulator Rsp Adapts Staphylococcus aureus Gene Expression to Acute Infection
Li, T., He, L., Song, Y. J., Villaruz, A. E., Joo, H., Liu, Q., Zhu, Y., Wang, Y., Qin, J., Otto, M. J., et al. (2015) · Infection and Immunity · doi:10.1128/iai.01088-15 · Cited by 34
“virulent clinical MRSA strain BD02-25, which belongs to pulsed-field type USA500 and 313 sequence type (ST) 8 (32).”
BackgroundMethodSelf-citationMartin, E., Çevik, C., & NUGENT, K. M. (2012) · Thrombosis Research · doi:10.1016/j.thromres.2012.06.013 · Cited by 36
Liebeke, M., & Lalk, M. (2013) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2013.11.017 · Cited by 37
Peters, P. J., Brooks, J. T., Limbago, B. M., Lowery, H. K., McAllister, S. K., Mindley, R., Fosheim, G. E., Gorwitz, R. J., Guest, J. L., Hageman, J. C., et al. (2010) · Epidemiology and Infection · doi:10.1017/s0950268810002013 · Cited by 33
“Interestingly, evolutionary studies suggest that USA300 and USA500 evolved from a common ancestor [37] suggesting that these strain types may share genetic determinants that favour colonization in this population.”
BackgroundComparison of Methicillin-resistant Versus Susceptible Staphylococcus aureus Pediatric Osteomyelitis
Davis, W. T., & Gilbert, S. R. (2018) · Journal of Pediatric Orthopaedics · doi:10.1097/bpo.0000000000001152 · Cited by 33
GPER activation protects against epithelial barrier disruption by Staphylococcus aureus α-toxin
Triplett, K. D., Pokhrel, S., Castleman, M. J., Daly, S. M., Elmore, B. O., Joyner, J. A., Sharma, G., Herbert, G., Campen, M. J., Hathaway, H. J., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-37951-3 · Cited by 31
Li, S., Sun, J., Zhang, J., Li, X., Tao, X., Wang, L., Sun, M., Liu, Y., Li, J., Qiao, Y., et al. (2013) · Apmis · doi:10.1111/apm.12105 · Cited by 32
Li, L., Pian, Y., Chen, S., Hao, H., Zheng, Y., Zhu, L., Xu, B., Liu, K., Li, M., Jiang, H., et al. (2016) · Scientific Reports · doi:10.1038/srep29373 · Cited by 32
“When mice were infected intravenously with 10 7 USA300 or USA300 Δ α , no mortality occurred in the two groups (data not shown).”
InfluentialSelf-citationInfluence of Magnolol on the Secretion of α-Toxin by Staphylococcus aureus
Xiang, H., Qiu, J., Wang, D., Jiang, Y., Xia, L., & Deng, X. (2010) · Molecules · doi:10.3390/molecules15031679 · Cited by 32
Stinear, T. P., Holt, K. E., Chua, K., Stepnell, J., Tuck, K. L., Coombs, G. W., Harrison, P. F., Seemann, T., & Howden, B. P. (2014) · Genome Biology and Evolution · doi:10.1093/gbe/evu022 · Cited by 30
“However, it is difficult to be certain of the individual contribution of any one factor, and comparative genomic and functional assessments suggest that the increased virulence of USA300 may be due to upregulation of core virulence genes such as Hla and phenol soluble modulins (Li et al. 2009).”
BackgroundTriantafyllopoulos, G. K., Soranoglou, V. G., Memtsoudis, S. G., & Poultsides, L. A. (2016) · World Journal of Orthopedics · doi:10.5312/wjo.v7.i9.546 · Cited by 31
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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