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• W2022673136 abstract "epidermolysis bullosa exfoliative toxin gamma-hemolysin B immunodominant antigen A iron-responsive surface determinant leukocidin peptidoglycan hydrolase median fluorescence intensity multiple-locus variable number of tandem repeats analysis endonuclease superantigens S. aureus surface protein G staphylococcal complement inhibitor staphylococcal enterotoxin TO THE EDITOR Patients with the blistering disease epidermolysis bullosa (EB) develop wounds that are highly susceptible to bacterial colonization. Recently, we reported that over 75% of the EB patients sampled at one particular point of time were colonized with Staphylococcus aureus (van der Kooi-Pol et al., 2012van der Kooi-Pol M.M. Veenstra-Kyuchukova Y.K. Duipmans J.C. et al.High genetic diversity of Staphylococcus aureus strains colonizing patients with epidermolysis bullosa.Exp Dermatol. 2012; 21: 463-466Crossref PubMed Scopus (25) Google Scholar). To determine possible changes in S. aureus colonization over time, swabs were collected from the nares, throats, and wounds of 61 EB patients at three time points during a period of ∼2 years. All S. aureus isolates were typed by multiple-locus variable number of tandem repeats analysis (MLVA) and spa typing. This revealed major fluctuations in the S. aureus types sampled from individual EB patients. In addition, blood samples were obtained from 13 EB patients to determine their IgG levels against 43 virulence factors or whole cells of S. aureus. Overall, the sera of EB patients contained higher anti-staphylococcal IgG levels than those of healthy individuals. Specifically, this applied to IgGs against nine important virulence factors, including the superantigens (SAgs) staphylococcal enterotoxin M (SEM), SEN, and SEO. Notably, EB patients carrying different S. aureus types contained higher levels of anti-staphylococcal antibodies than EB patients colonized by only one type. Our findings suggest that the immune system of EB patients is heavily challenged with S. aureus antigens. EB is a genetic blistering disease that renders patients susceptible to colonization by the opportunistic pathogen Staphylococcus aureus (Brandling-Bennett and Morel, 2010Brandling-Bennett H.A. Morel K.D. Common wound colonizers in patients with epidermolysis bullosa.Pediatr Dermatol. 2010; 27: 25-28Crossref PubMed Scopus (31) Google Scholar; Graber et al., 2011Graber C.J. Shane A.L. Weintrub P. et al.Clonality of Staphylococcus aureus colonization over time in attendees of a camp for children with chronic dermatoses.Pediatr Dermatol. 2011; 28: 519-523Crossref PubMed Scopus (11) Google Scholar; Pope et al., 2012Pope E. Lara-Corrales I. Mellerio J. et al.A consensus approach to wound care in epidermolysis bullosa.J Am Acad Dermatol. 2012Abstract Full Text Full Text PDF Scopus (112) Google Scholar). Recently, we observed that all EB patients with chronic wounds, and 75% of patients without chronic wounds, were colonized with S. aureus (van der Kooi-Pol et al., 2012van der Kooi-Pol M.M. Veenstra-Kyuchukova Y.K. Duipmans J.C. et al.High genetic diversity of Staphylococcus aureus strains colonizing patients with epidermolysis bullosa.Exp Dermatol. 2012; 21: 463-466Crossref PubMed Scopus (25) Google Scholar). In contrast, only ∼30% of the healthy human population carries this pathogen (Wertheim et al., 2005Wertheim H.F. Melles D.C. Vos M.C. et al.The role of nasal carriage in Staphylococcus aureus infections.Lancet Infect Dis. 2005; 5: 751-762Abstract Full Text Full Text PDF PubMed Scopus (1784) Google Scholar). Persistent S. aureus carriers have an increased risk for staphylococcal infections but, compared with noncarriers, their risk of death due to bacteremia is lower (Wertheim et al., 2004Wertheim H.F. Vos M.C. Ott A. et al.Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers.Lancet. 2004; 364: 703-705Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar). This may relate to increased levels of protective anti-staphylococcal antibodies upon long-term exposure to colonizing strains (Kolata et al., 2011Kolata J. Bode L.G. Holtfreter S. et al.Distinctive patterns in the human antibody response to Staphylococcus aureus bacteremia in carriers and non-carriers.Proteomics. 2011; 11: 3914-3927Crossref PubMed Scopus (59) Google Scholar). Furthermore, anti-staphylococcal antibody levels were shown to increase strongly during bacteremia (Verkaik et al., 2010Verkaik N.J. Boelens H.A. de Vogel C.P. et al.Heterogeneity of the humoral immune response following Staphylococcus aureus bacteremia.Eur J Clin Microbiol Infect Dis. 2010; 29: 509-518Crossref PubMed Scopus (65) Google Scholar; Kolata et al., 2011Kolata J. Bode L.G. Holtfreter S. et al.Distinctive patterns in the human antibody response to Staphylococcus aureus bacteremia in carriers and non-carriers.Proteomics. 2011; 11: 3914-3927Crossref PubMed Scopus (59) Google Scholar). As high exposure to S. aureus is a potential health risk for EB patients, our present studies were first aimed at defining their S. aureus population over time and, second, at determining their anti-staphylococcal IgG levels. On the basis of informed consent, 61 EB patients from the Dutch Epidermolysis Bullosa Registry were included in our studies (Supplementary Methods online). S. aureus colonization was determined in three rounds of sampling at half-yearly intervals. In each round, swabs were collected from three wounds, the left and right anterior nares, and the throat. A total of 43 EB patients participated in the second sampling round, 40 in the third, and 35 patients participated in all three sampling rounds. Overall, we identified 101 different S. aureus types by molecular typing with MLVA (Supplementary Methods online and Supplementary Table S1 online). Only 18 of these MLVA types were encountered in all rounds (Figure 1a). One hundred and eighteen strains were also spa typed, revealing 48 different spa types (Supplementary Table S1 online). Next, we compared the variations in S. aureus types isolated from individual EB patients over time. This revealed that the same MLVA type was identified on ∼42.5% of all sampled patients with minor variations for different sites of sampling (Figure 1b). Furthermore, 58.3% of the patients with chronic wounds and 43.5% of the patients without chronic wounds carried alternating S. aureus MLVA types over time. In 8.7% of the patients without chronic wounds, a different MLVA type was encountered in each sampling round. These findings show that the included EB patients are continuously challenged by different S. aureus types and that the carried S. aureus population can change rapidly. This seems to challenge the classical dogma that persistent carriers are mainly colonized by one S. aureus type (Wertheim et al., 2005Wertheim H.F. Melles D.C. Vos M.C. et al.The role of nasal carriage in Staphylococcus aureus infections.Lancet Infect Dis. 2005; 5: 751-762Abstract Full Text Full Text PDF PubMed Scopus (1784) Google Scholar). However, our studies specifically address a patient group that is highly susceptible to S. aureus owing to continuous skin defects, which is different from the situation in healthy individuals. Download .pdf (.67 MB) Help with pdf files Supplementary Information To assess the anti-staphylococcal IgG levels in EB patients, we first performed whole-cell ELISAs using an S. aureus mutant lacking the IgG-binding proteins Spa and Sbi, and IgGs isolated from patients with chronic wounds. Sera from healthy donors were used as controls. This revealed that EB patient sera contained significantly higher anti-staphylococcal IgG levels than the controls (Supplementary Figure S1 online). To determine specific responses, the levels of serum IgGs from 13 EB patients against 43 purified S. aureus antigens were measured using Luminex technology (Figure 2). As controls, the sera from 14 age-matched healthy individuals were used. For most antigens, the median fluorescence intensities (MFI) were higher in EB patients than in the control group. In particular, the MFI levels for IgGs against the surface proteins IsdA (iron-responsive surface determinant A) and SasG (S. aureus surface protein G), the secreted proteins IsaA (immunodominant antigen A), SCIN (staphylococcal complement inhibitor), Nuc (endonuclease), and LytM (peptidoglycan hydrolase), and the SAgs SEM, SEN, and SEO were statistically significantly higher in EB patients. The increased IgG levels against IsaA, SCIN, Nuc, and LytM could be explained by the fact that these proteins are expressed by many S. aureus types (Ziebandt et al., 2010Ziebandt A.K. Kusch H. Degner M. et al.Proteomics uncovers extreme heterogeneity in the Staphylococcus aureus exoproteome due to genomic plasticity and variant gene regulation.Proteomics. 2010; 10: 1634-1644Crossref PubMed Scopus (118) Google Scholar). In addition, the egc gene cluster–encoded SAgs SEM, SEN, and SEO are among the most prevalent SAgs of S. aureus (52–66%) (Holtfreter et al., 2007Holtfreter S. Grumann D. Schmudde M. et al.Clonal distribution of superantigen genes in clinical Staphylococcus aureus isolates.J Clin Microbiol. 2007; 45: 2669-2680Crossref PubMed Scopus (191) Google Scholar). Intriguingly, persistent carriers, bacteremia patients, and furunculosis patients were found to develop no, or only low levels of, antibodies against these SAgs (Grumann et al., 2011Grumann D. Ruotsalainen E. Kolata J. et al.Characterization of infecting strains and superantigen-neutralizing antibodies in Staphylococcus aureus bacteremia.Clin Vaccine Immunol. 2011; 18: 487-493Crossref PubMed Scopus (30) Google Scholar; Holtfreter et al., 2011Holtfreter S. Jursa-Kulesza J. Masiuk H. et al.Antibody responses in furunculosis patients vaccinated with autologous formalin-killed Staphylococcus aureus.Eur J Clin Microbiol Infect Dis. 2011; 30: 707-717Crossref PubMed Scopus (30) Google Scholar; Burian et al., 2012Burian M. Grumann D. Holtfreter S. et al.Expression of staphylococcal superantigens during nasal colonization is not sufficient to induce a systemic neutralizing antibody response in humans.Eur J Clin Microbiol Infect Dis. 2012; 31: 251-256Crossref PubMed Scopus (22) Google Scholar). This suggests that EB patients are more significantly challenged by egc SAgs than healthy carriers and bacteremia or furunculosis patients. To determine whether carriage of multiple S. aureus strains has an impact on anti-staphylococcal IgG levels, we compared patients colonized by one MLVA type (n=7) with patients colonized by multiple MLVA types (n=5). Interestingly, the highest MFI levels were observed for IgG’s from patients carrying multiple MLVA types. This was particularly evident for IgGs against IsdA, LukD (leukocidin D), HlgB (gamma-hemolysin B), LytM, LukS, LukF, and ETA (exfoliative toxin A) (Figure 2b). Notably, the incidence of LukS/F is very low, and thus, conceivably, the respective Luminex signals represent cross-reactive IgGs against the more common HlgA/B or LukE/D proteins (Gravet et al., 1998Gravet A. Colin D.A. Keller D. et al.Characterization of a novel structural member, LukE-LukD, of the bi-component staphylococcal leucotoxins family.FEBS Lett. 1998; 436: 202-208Crossref PubMed Scopus (145) Google Scholar). A significant correlation between anti-staphylococcal IgG levels in serum, wound fluid, and sterile blister fluid was revealed in samples from one EB patient (Supplementary Figure S2 online). Here, the largest difference concerned 4-fold lowered anti-IsaA levels in wound fluid. This implies that future studies on anti-staphylococcal immune responses in EB patients can be based on noninvasively sampled wound fluid. In conclusion, EB patients are highly challenged with very diverse S. aureus types, and carriage of multiple S. aureus types seems to elicit the highest humoral responses in these patients. However, we cannot exclude the alternative possibility of increased humoral and reduced cell-mediated immunity in EB patients, which might have an impact on S. aureus carriage. Notably, EB patients do not frequently suffer from S. aureus bacteremia, and none of the patients who donated blood was treated for staphylococcal bacteremia in the 5 years before blood donation. This suggests that their high anti-staphylococcal antibody titers may be protective against invasive S. aureus infections, which would be consistent with the protective effects of IsaA-specific antibodies in mice (Lorenz et al., 2011Lorenz U. Lorenz B. Schmitter T. et al.Functional antibodies targeting IsaA of Staphylococcus aureus augment host immune response and open new perspectives for antibacterial therapy.Antimicrob Agents Chemother. 2011; 55: 165-173Crossref PubMed Scopus (40) Google Scholar). We thank the anonymous patients with EB from the Dutch Epidermolysis Bullosa Registry and health-care workers from the Department of Dermatology at the UMCG for their participation in the present study, as well as the technicians of the Department of Medical Microbiology at the UMCG for excellent technical support. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid" @default.
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• W2022673136 title "High Anti-Staphylococcal Antibody Titers in Patients with Epidermolysis Bullosa Relate to Long-Term Colonization with Alternating Types of Staphylococcus aureus" @default.
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