Skip to main content
  • Loading metrics

Impact of Bacterial and Human Genetic Variation on Staphylococcus aureus Infections

  • Julia A. Messina,

    Affiliations Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America, Duke Clinical Research Institute, Duke University, Durham, North Carolina, United States of America

  • Joshua T. Thaden,

    Affiliation Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America

  • Batu K. Sharma-Kuinkel,

    Affiliation Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America

  • Vance G. Fowler Jr.

    Affiliations Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina, United States of America, Duke Clinical Research Institute, Duke University, Durham, North Carolina, United States of America

The clinical diversity of syndromes caused by Staphylococcus aureus arises from a complex interplay between host and pathogen. Genetic variation can result in increased susceptibility to infection within the host and an increased capacity for virulence within the pathogen, resulting in a wide array of clinical syndromes. This review presents evidence for the role of bacterial and human genetic variation in influencing the clinical outcome of S. aureus infections.

What Role Does Bacterial Genetic Variation Play in S. aureus Infections?

Genetic variation that encodes for virulence, antibiotic resistance, and host adaptation can be introduced through horizontal transfer of mobile genetic elements (MGE)—including bacteriophages, pathogenicity islands (SaPI), plasmids, transposons, and cassette chromosomes—between S. aureus isolates [1]. MGE tend to distribute asymmetrically within S. aureus isolates of the same genetic background, or clonal complex (CC). Staphylococcal toxic shock syndrome, a disease of unchecked inflammatory cascade induced by superantigen toxic shock syndrome toxin-1 (TSST-1), provides a classic example of the potential impact of MGE on clinical virulence of S. aureus. The gene that encodes for TSST-1, tst, is located on the MGE SaPI1 and is spread horizontally in distinct CCs of clinical S. aureus isolates [2,3].

Asymmetric clustering of adhesins and toxins within specific S. aureus CCs may be associated with an increased risk for other types of S. aureus infection. S. aureus from CC5 and CC30 genotypes were significantly associated with hematogenous complications, including left-sided native valve infective endocarditis (IE), when compared with clinical S. aureus isolates of other genotypes from the same referral area [4]. The association between CC30 and IE was also found in an international collection of geographically matched S. aureus isolates from patients with either left-sided IE or soft tissue infection [5]. In rabbit models, S. aureus isolates belonging to the USA200, a genotype defined by pulsed-field gel electrophoresis that approximately corresponds to CC30 in the multi-locus sequence typing strategy, were significantly more likely to cause IE but less likely to cause lethal sepsis than isolates from either USA300 (CC8) or USA400 (CC1) genetic backgrounds [6]. The attenuated sepsis virulence of CC30 has also been documented in murine models [79].

What makes the CC30 clonotype distinct? The reduced sepsis virulence of CC30 is at least partially explained by a stop codon mutation in hla, the gene in S. aureus that encodes for the potent virulence factor alpha toxin [7]. A number of other genes also appear to be expressed differently in CC30 isolates. Using in vitro RNA sequencing, clinically derived CC30 S. aureus differed from isolates of other lineages by significantly higher expression of protein A (spa), putative membrane proteins (SAR2274, SAR2275), and exported proteins (SAR2016, SAR0437, and SAR0694), as well as significantly lower expression levels of genes within the pyrimidine biosynthesis pathway (carB, pyrC, pyrR, pyrE, and pyrF), iron repressible ABC transport (SAR0641, SAR0642, and SAR0643), and an azoreductase (acpD) [9]. Recently, CC30 was also shown to express an allelic variant of the key toxin Phenol-Soluble Modulin α3 that conferred reduced chemotactic potential and increased hematogenous seeding [8]. Which of these differences, if any, contribute to CC30’s association with specific clinical syndromes is an area of ongoing investigation.

Bacterial genetic variation can also occur on the level of polymorphisms within specific genes that contribute to the virulence of S. aureus. For example, fibronectin-binding protein A (FNBPA), encoded by fnbA, is thought to play a critical role in the initiation of IE [10]. FNBPA binds to human fibronectin, a protein that deposits on sites of endothelial disruption as well as the endovascular leads of permanent pacemakers and defibrillators. We evaluated the possibility that genetic variation within the binding regions of fnbA of S. aureus bloodstream isolates would be associated with an increased risk of cardiac device infection (CDI) in patients who developed S. aureus bacteremia [11]. Three nonsynonymous single nucleotide polymorphisms (SNPs), E652D, H782Q, and K786N, in the binding region of fnbA of bloodstream S. aureus isolates, were significantly associated with an increased risk of CDI in the source patient. Using atomic force microscopy (AFM), isolates containing these SNPs exhibited significantly higher frequency and strength of binding to fibronectin. Synthesized peptides containing two of the three polymorphisms (H782Q and K786N double mutant) exhibited 34% higher binding activity than the wild type by AFM. In silico molecular dynamics simulations demonstrated that residues of each of the three polymorphisms in FNBPA formed extra hydrogen bonds with fibronectin, providing a potential explanation for this observation of higher binding affinity. The association between specific fnbA SNPs and an increased risk of CDI was recently validated in a cohort of German patients with cardiac devices and S. aureus bacteremia [12]. Interestingly, however, no similar association was seen in patients with prosthetic joints and S. aureus bacteremia [13]. The apparent specificity of association between fnbA SNPs and infection type may be due in part to the fact that arthroplasties lack a fibrin sheath, the fibronectin-rich coating present on endovascular leads of cardiac devices [14].

What Is the Role of Host Genetic Variation in S. aureus Infections?

Host genetic characteristics can also influence the host–pathogen interaction (Table 1). Higher rates of S. aureus infections have been observed in genetically distinct ethnic populations [1518]. Patients with rare genetic disorders such as Chédiak-Higashi syndrome [19], Hyper-IgE syndrome [20], IRAK-4 deficiency [21], MyD88 deficiency [22], and chronic granulomatous disease [23] also exhibit susceptibility to S. aureus infection. Finally, different strains of sheep [24], cattle [25], and mice [26] have different susceptibility to S. aureus infection, sepsis, and death.

Table 1. Evidence for genetic variation and Staphylococcus aureus infection.

Despite this indirect evidence, none of the handful of studies published to date have confirmed the role of human genetic variation in S. aureus colonization and infection. In a study of adult Danish twins, investigators report S. aureus nasal carriage in 26.3% of the 617 twin pairs studied, with a concordance rate among monozygotic twins only slightly greater than the overall prevalence [27]. No sign of heritability was observed, and concordance did not vary based upon monozygotic or dizygotic lineage or gender.

Three genome-wide association studies (GWAS) have looked at potential associations between common genetic variants and human susceptibility to S. aureus infection. Nelson et al. used a GWAS approach to compare 361 Caucasian patients with healthcare-associated S. aureus bacteremia (SAB) to 699 hospitalized controls without S. aureus infection [28]. No genome-wide significant common variant was found to be associated with risk of acquiring SAB or severity of SAB (Bonferroni correction, p < 9.2x10-8). However, upon excluding the interaction between host SNP and bacterial CC, the investigators did note that rs2043436, an SNP located on the candidate gene CDON, which encodes a cell surface receptor that is a member of the immunoglobulin family, was associated with severity of infection at the level of p = 1.64x10-6. Ye et al. (2014) used GWAS to compare 309 cases with S. aureus infection to 2,925 uninfected adult Northern European control subjects. Again, none of the SNPs identified met genome-wide significance (p < 5x10-8). Four SNPs approached significance at a level of p < 10−5. Genes associated with these SNPs were PDE4B (rs2455012), involved in bacterial-induced inflammation; TXNRD2 (rs3804047), involved in the maintenance of thioredoxin in a reduced state; VRK1, which encodes a serine and/or threonine kinase; BCL11B (rs7152530), which encodes a repressor involved in T cell development; and PNPLA5 (rs470093), involved in autophagosome function.

Most recently, DeLorenze et al. provide the first GWAS evidence of human genetic susceptibility to S. aureus infection. The investigators genotyped a Caucasian population of 4,701 cases of S. aureus infection and 45,344 matched controls [29]. Two imputed SNPs (rs115231074: p = 1.3 x 10−10 and rs35079132: p = 3.8 x 10−8) achieved genome-wide significance, and one adjacent genotyped SNP was nearly significant genome-wide (rs4321864: p = 8.8 x 10−8). These polymorphisms were located near HLA-DRA and HLA-DRB1 genes on chromosome 6 in the HLA class II region. Significant evidence supports the possibility that HLA class II haplotypes may influence human susceptibility to S. aureus infection. First, specific HLA haplotypes (HLA II DR14 and/or DQ5) are associated with susceptibility to invasive Streptococcus pyogenes infection in patients [30] and determine severity of response to bacterial superantigens from both S. pyogenes [31] and S. aureus [32]. Second, S. aureus superantigens, including TSST-1, bind to the HLA II DR1 molecule [33] and are critical in the development of S. aureus bacteremia and endocarditis [34]. Third, nasal carriage of S. aureus is associated with the HLA-DR3 and HLA-DR7 class II serotypes [35]. Finally, polymorphisms in HLA-DRB1 are strongly associated with rheumatoid arthritis [36], an inflammatory disease characterized by a high risk of S. aureus infection.

What Are the Future Directions in the Study of Genetic Variation and S. aureus Infection?

Studying the impact of bacterial genetic variation on infection severity in patients will improve our understanding of pathogenesis and will ultimately inform vaccine development and future therapeutic targets. Similarly, insights into the role of human genetic variation on invasive S. aureus infection will identify high-risk populations in whom expensive and invasive diagnostic and therapeutic strategies can be invested in an increasingly cost-conscious healthcare environment. Achieving these potential advances, however, will require overcoming a number of scientific and practical limitations. First, virulence in S. aureus is noteworthy for its redundancy, with many proteins exhibiting overlapping function. For example, at least four S. aureus proteins have the capacity to bind fibrinogen: FNBPA, clumping factor A, clumping factor B, and bone sialoprotein-binding protein [37]. At least two of these proteins, FNBPA and fibronectin-binding protein B, also bind to fibronectin. Next, specific bacterial genes are likely to only be relevant in certain types of infection. For example, genes involved in infections initiated by bacterial binding of host tissues (e.g., IE and osteoarticular infections) are likely to differ from those involved in toxin-mediated syndromes (e.g., toxic shock syndrome, staphylococcal scalded skin syndrome, and necrotizing fasciitis). Finally, genome sequencing of isolates causing invasive disease has shown considerable within-host diversity in S. aureus, including multiple mutations in the same genes [38]. This within-host diversity may rise and fall over time and be biologically relevant, resulting in inactivation of global virulence regulators and changes in phage copy number.

Given these multiple sources of potential confusion, translational investigations focused on staphylococcal pathogenesis should strictly minimize sources of study variation. Bacterial genetic variation could be reduced by limiting studies to infections caused by a specific genotype of S. aureus. Variation introduced by the inclusion of multiple infection types (e.g., IE versus pneumonia versus soft tissue infection) can be reduced by focusing on a single, carefully defined clinical syndrome. For example, focusing on complementary bacterial receptors and host ligands, such as S. aureus FNBPA and human fibronectin in patients with hematogenous cardiac device-associated infections, reduces the possibility of a false negative result by minimizing the number of host–pathogen interactions at play. Finally, human genetic variation may be minimized by limiting study populations to single ethnic backgrounds when conducting human genotyping studies.

In conclusion, substantial evidence for the impact of genetic variation on susceptibility to S. aureus infection exists. Within the pathogen, evidence is found at the clonal, gene, and SNP levels. Observational studies of genetically distinct ethnic populations and inbred animals also suggest the importance of host genetic variation on the initiation and severity of S. aureus infection. More translational studies investigating the role of host genetic variability in S. aureus infection are warranted. The confounding impact of heterogeneity introduced into genetic association studies in S. aureus can be minimized by limiting study populations by infection type, pathogen genotype, and host ethnicity.


The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  1. 1. Lindsay JA. Staphylococcus aureus genomics and the impact of horizontal gene transfer. International Journal of Medical Microbiology: IJMM. 2014;304(2):103–9. pmid:24439196.
  2. 2. Lindsay JA, Ruzin A, Ross HF, Kurepina N, Novick RP. The gene for toxic shock toxin is carried by a family of mobile pathogenicity islands in Staphylococcus aureus. Molecular Microbiology. 1998;29(2):527–43. pmid:9720870.
  3. 3. Ruzin A, Lindsay J, Novick RP. Molecular genetics of SaPI1—a mobile pathogenicity island in Staphylococcus aureus. Molecular Microbiology. 2001;41(2):365–77. pmid:11489124.
  4. 4. Fowler VG Jr., Nelson CL, McIntyre LM, Kreiswirth BN, Monk A, Archer GL, et al. Potential associations between hematogenous complications and bacterial genotype in Staphylococcus aureus infection. The Journal of Infectious Diseases. 2007;196(5):738–47. pmid:17674317.
  5. 5. Nienaber JJ, Sharma Kuinkel BK, Clarke-Pearson M, Lamlertthon S, Park L, Rude TH, et al. Methicillin-susceptible Staphylococcus aureus endocarditis isolates are associated with clonal complex 30 genotype and a distinct repertoire of enterotoxins and adhesins. The Journal of Infectious Diseases. 2011;204(5):704–13. pmid:21844296; PubMed Central PMCID: PMC3156104.
  6. 6. Spaulding AR, Satterwhite EA, Lin YC, Chuang-Smith ON, Frank KL, Merriman JA, et al. Comparison of Staphylococcus aureus strains for ability to cause infective endocarditis and lethal sepsis in rabbits. Frontiers in Cellular and Infection Microbiology. 2012;2:18. pmid:22919610; PubMed Central PMCID: PMC3417574.
  7. 7. DeLeo FR, Kennedy AD, Chen L, Bubeck Wardenburg J, Kobayashi SD, Mathema B, et al. Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(44):18091–6. pmid:22025717; PubMed Central PMCID: PMC3207694.
  8. 8. Cheung GY, Kretschmer D, Duong AC, Yeh AJ, Ho TV, Chen Y, et al. Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection. PLoS Pathog. 2014;10(8):e1004298. pmid:25144687; PubMed Central PMCID: PMCPMC4140855.
  9. 9. Sharma-Kuinkel BK, Mongodin EF, Myers JR, Vore KL, Canfield GS, Fraser CM, et al. Potential Influence of Staphylococcus aureus Clonal Complex 30 Genotype and Transcriptome on Hematogenous Infections. Open Forum Infectious Diseases. 2015;2(3):ofv093. pmid:26213692; PubMed Central PMCID: PMCPMC4512144.
  10. 10. Peacock SJ, Foster TJ, Cameron BJ, Berendt AR. Bacterial fibronectin-binding proteins and endothelial cell surface fibronectin mediate adherence of Staphylococcus aureus to resting human endothelial cells. Microbiology. 1999;145 (Pt 12):3477–86. pmid:10627045.
  11. 11. Lower SK, Lamlertthon S, Casillas-Ituarte NN, Lins RD, Yongsunthon R, Taylor ES, et al. Polymorphisms in fibronectin binding protein A of Staphylococcus aureus are associated with infection of cardiovascular devices. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(45):18372–7. pmid:22025727; PubMed Central PMCID: PMC3215016.
  12. 12. Hos NJ, Rieg S, Kern WV, Jonas D, Fowler VG, Higgins PG, et al. Amino acid alterations in fibronectin binding protein A (FnBPA) and bacterial genotype are associated with cardiac device related infection in Staphylococcus aureus bacteraemia. The Journal of Infection. 2015;70(2):153–9. pmid:25246358.
  13. 13. Eichenberger EM, Thaden JT, Sharma-Kuinkel B, Park LP, Rude TH, Ruffin F, et al. Polymorphisms in Fibronectin Binding Proteins A and B among Staphylococcus aureus Bloodstream Isolates Are Not Associated with Arthroplasty Infection. PLoS ONE. 2015;10(11):e0141436. pmid:26606522.
  14. 14. Herrmann M, Vaudaux PE, Pittet D, Auckenthaler R, Lew PD, Schumacher-Perdreau F, et al. Fibronectin, fibrinogen, and laminin act as mediators of adherence of clinical staphylococcal isolates to foreign material. The Journal of Infectious Diseases. 1988;158(4):693–701. pmid:3171224.
  15. 15. Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298(15):1763–71. pmid:17940231.
  16. 16. Hill PC, Wong CG, Voss LM, Taylor SL, Pottumarthy S, Drinkovic D, et al. Prospective study of 125 cases of Staphylococcus aureus bacteremia in children in New Zealand. The Pediatric Infectious Disease Journal. 2001;20(9):868–73. pmid:11734766.
  17. 17. Maguire GP, Arthur AD, Boustead PJ, Dwyer B, Currie BJ. Clinical experience and outcomes of community-acquired and nosocomial methicillin-resistant Staphylococcus aureus in a northern Australian hospital. The Journal of Hospital Infection. 1998;38(4):273–81. pmid:9602976.
  18. 18. Embil J, Ramotar K, Romance L, Alfa M, Conly J, Cronk S, et al. Methicillin-resistant Staphylococcus aureus in tertiary care institutions on the Canadian prairies 1990–1992. Infection Control and Hospital Epidemiology. 1994;15(10):646–51. pmid:7844335.
  19. 19. Komiyama A, Saitoh H, Yamazaki M, Kawai H, Miyagawa Y, Akabane T, et al. Hyperactive phagocytosis by circulating neutrophils and monocytes in Chediak-Higashi syndrome. Scandinavian Journal of Haematology. 1986;37(2):162–7. pmid:3764339.
  20. 20. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 mutations in the hyper-IgE syndrome. The New England Journal of Medicine. 2007;357(16):1608–19. pmid:17881745.
  21. 21. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003;299(5615):2076–9. pmid:12637671.
  22. 22. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321(5889):691–6. pmid:18669862; PubMed Central PMCID: PMC2688396.
  23. 23. Ben-Ari J, Wolach O, Gavrieli R, Wolach B. Infections associated with chronic granulomatous disease: linking genetics to phenotypic expression. Expert Review of Anti-Infective Therapy. 2012;10(8):881–94. pmid:23030328.
  24. 24. Bonnefont CM, Rainard P, Cunha P, Gilbert FB, Toufeer M, Aurel MR, et al. Genetic susceptibility to S. aureus mastitis in sheep: differential expression of mammary epithelial cells in response to live bacteria or supernatant. Physiological Genomics. 2012;44(7):403–16. pmid:22337903.
  25. 25. Griesbeck-Zilch B, Osman M, Kuhn C, Schwerin M, Bruckmaier RH, Pfaffl MW, et al. Analysis of key molecules of the innate immune system in mammary epithelial cells isolated from marker-assisted and conventionally selected cattle. Journal of Dairy Science. 2009;92(9):4621–33. pmid:19700725.
  26. 26. Ahn SH, Deshmukh H, Johnson N, Cowell LG, Rude TH, Scott WK, et al. Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses. PLoS Pathog. 2010;6(9):e1001088. pmid:20824097; PubMed Central PMCID: PMC2932726.
  27. 27. Andersen PS, Pedersen JK, Fode P, Skov RL, Fowler VG Jr., Stegger M, et al. Influence of host genetics and environment on nasal carriage of Staphylococcus aureus in danish middle-aged and elderly twins. The Journal of Infectious Diseases. 2012;206(8):1178–84. pmid:22872733; PubMed Central PMCID: PMC3448969.
  28. 28. Nelson CL, Pelak K, Podgoreanu MV, Ahn SH, Scott WK, Allen AS, et al. A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting. BMC Infectious Diseases. 2014;14:83. pmid:24524581; PubMed Central PMCID: PMC3928605.
  29. 29. DeLorenze GN, Nelson CL, Scott WK, Allen AS, Ray GT, Tsai AL, et al. Polymorphisms in HLA Class II Genes Are Associated With Susceptibility to Staphylococcus aureus Infection in a White Population. The Journal of Infectious Diseases. 2015 Oct 8. Epub ahead of print. pmid:26450422.
  30. 30. Kotb M, Norrby-Teglund A, McGeer A, El-Sherbini H, Dorak MT, Khurshid A, et al. An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nature Medicine. 2002;8(12):1398–404. pmid:12436116.
  31. 31. Nooh MM, El-Gengehi N, Kansal R, David CS, Kotb M. HLA transgenic mice provide evidence for a direct and dominant role of HLA class II variation in modulating the severity of streptococcal sepsis. Journal of Immunology. 2007;178(5):3076–83. pmid:17312154.
  32. 32. Llewelyn M, Sriskandan S, Peakman M, Ambrozak DR, Douek DC, Kwok WW, et al. HLA class II polymorphisms determine responses to bacterial superantigens. Journal of Immunology. 2004;172(3):1719–26. pmid:14734754.
  33. 33. Kim J, Urban RG, Strominger JL, Wiley DC. Toxic shock syndrome toxin-1 complexed with a class II major histocompatibility molecule HLA-DR1. Science. 1994;266(5192):1870–4. pmid:7997880.
  34. 34. Salgado-Pabon W, Breshears L, Spaulding AR, Merriman JA, Stach CS, Horswill AR, et al. Superantigens are critical for Staphylococcus aureus Infective endocarditis, sepsis, and acute kidney injury. MBio. 2013;4(4). pmid:23963178; PubMed Central PMCID: PMCPMC3747586.
  35. 35. Kinsman OS, McKenna R, Noble WC. Association between histocompatability antigens (HLA) and nasal carriage of Staphylococcus aureus. Journal of Medical Microbiology. 1983;16(2):215–20. pmid:6573514.
  36. 36. Thomson W, Harrison B, Ollier B, Wiles N, Payton T, Barrett J, et al. Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study. Arthritis & Rheumatism. 1999;42(4):757–62. pmid:10211891.
  37. 37. Foster TJ, Geoghegan JA, Ganesh VK, Hook M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nature Reviews Microbiology. 2014;12(1):49–62. pmid:24336184.
  38. 38. Paterson GK, Harrison EM, Murray GG, Welch JJ, Warland JH, Holden MT, et al. Capturing the cloud of diversity reveals complexity and heterogeneity of MRSA carriage, infection and transmission. Nature Communications. 2015;6:6560. pmid:25814293; PubMed Central PMCID: PMC4389252.
  39. 39. Ye Z, Vasco DA, Carter TC, Brilliant MH, Schrodi SJ, Shukla SK. Genome wide association study of SNP-, gene-, and pathway-based approaches to identify genes influencing susceptibility to Staphylococcus aureus infections. Frontiers in Genetics. 2014;5:125. pmid:24847357; PubMed Central PMCID: PMC4023021.
  40. 40. Miller CE, Batra R, Cooper BS, Patel AK, Klein J, Otter JA, et al. An association between bacterial genotype combined with a high-vancomycin minimum inhibitory concentration and risk of endocarditis in methicillin-resistant Staphylococcus aureus bloodstream infection. Clinical Infectious Diseases. 2012;54(5):591–600. pmid:22186774; PubMed Central PMCID: PMC3275756.
  41. 41. Yamasaki O, Yamaguchi T, Sugai M, Chapuis-Cellier C, Arnaud F, Vandenesch F, et al. Clinical manifestations of staphylococcal scalded-skin syndrome depend on serotypes of exfoliative toxins. Journal of Clinical Microbiology. 2005;43(4):1890–3. pmid:15815014; PubMed Central PMCID: PMC1081326.