Colonization With Staphylococcus aureus in Atopic Dermatitis Patients: Attempts to Reveal the Unknown

fmicb-11-567090 December 31, 2020 Time: 11:20 # 1 REVIEW published: 11 January 2021 doi: 10.3389/fmicb.2020.567090 Edited by: Fabian Cieplik, University Medical Center Regensburg, Germany Reviewed by: Teruaki Nakatsuji, University of California, San Diego, United States Michael Otto, National Institutes of Health (NIH), United States *Correspondence: Joanna Nakonieczna joanna.nakonieczna @biotech.ug.edu.pl orcid.org/0000-0002-2420-664X Specialty section: This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology Received: 29 May 2020 Accepted: 14 December 2020 Published: 11 January 2021 Citation: Ogonowska P, Gilaberte Y, Bara ´ nska-Rybak W and Nakonieczna J (2021) Colonization With Staphylococcus aureus in Atopic Dermatitis Patients: Attempts to Reveal the Unknown. Front. Microbiol. 11:567090. doi: 10.3389/fmicb.2020.567090 Colonization With Staphylococcus aureus in Atopic Dermatitis Patients: Attempts to Reveal the Unknown Patrycja Ogonowska1, Yolanda Gilaberte2, Wioletta Bara ´ nska-Rybak3and Joanna Nakonieczna1* 1Laboratory of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology University of Gda ´ nsk and Medical University of Gda ´ nsk, Gda ´ nsk, Poland, 2Department of Dermatology, University Hospital Miguel Servet, Zaragoza, Spain, 3Department of Dermatology, Venereology and Allergology, Medical University of Gda ´ nsk, Gda ´ nsk, Poland Atopic dermatitis (AD) patients are massively colonized with Staphylococcus aureus (S. aureus) in lesional and non-lesional skin. A skin infection may become systemic if left untreated. Of interest, the incidence of multi-drug resistant S. aureus (MRSA) in AD patients is higher as compared to a healthy population, which makes treatment even more challenging. Information on the specific genetic background of S. aureus accompanying and/or causing AD flares would be of great importance in terms of possible treatment option development. In this review, we summarized the data on the prevalence of S. aureus in general in AD skin, and the prevalence of specific clones that might be associated with flares of eczema. We put our special interest in the presence and role of staphylococcal enterotoxins as important virulence factors in the epidemiology of AD-derived S. aureus. Also, we summarize the present and potentially useful future anti-staphylococcal treatment. Keywords: epidemiology of S. aureus, MRSA, staphylococcal enterotoxins, antistaphylococcal photodynamic treatment, virulence factor INTRODUCTION Atopic dermatitis (AD), also known as atopic eczema, is a chronic and relapsing inflammatory skin disorder. It may coexist with other atopic conditions: allergic rhinitis (hay fever), bronchial asthma and food allergy. AD mainly affects infants and young children. Nevertheless, it can persist or appear during puberty and adulthood. AD occurs commonly in 15–30% of children and 2–10% of adults worldwide (Silverberg, 2017). In 1980, Hanifin and Rajka proposed criteria for diagnosing AD. According to the published guidelines, patients diagnosed with AD should present three or more basic features (e.g., pruritus, lichenification, atopic history) and three or more minor features (e.g., xerosis, early age of onset, food intolerance) (Hanifin and Rajka, 1980). Furthermore, various scoring systems have been established to measure disease severity. SCORAD (Severity Scoring Index of Atopic Dermatitis) evaluates the intensity of atopic signs in general in addition to the symptoms (pruritus and sleep) (Kunz et al., 1997), whereas EASI (Eczema Area and Severity Index) evaluates the severity of AD in four different parts of the body (head and neck, upper limbs, trunk and lower limbs) (Hanifin et al., 2001;Housman et al., 2002). SASSAD (Six Area Six Sign Atopic Dermatitis Atopic Score) less used includes six signs of AD (cracking, dryness, erythema, excoriation, exudation, and lichenification), their severity in a four-point scale (0—absent, 1—mild, 2—moderate and 3—severe) on the most Frontiers in Microbiology | www.frontiersin.org 1January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 2 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis FIGURE 1 | Various scoring systems for diagnosing atopic dermatitis. following sites of different parts of the body (head and neck, arms, hands, trunk, legs, and feet) (Figure 1;Berth-Jones and BerthJones, 1996). Currently, AD is considered a multifactorial skin disorder, with still not fully understood pathogenesis. The development of AD is a result of interactions between skin barrier defects and genetic, immunological and environmental factors (e.g., dust mite, tobacco smoke, soap, diet, air pollution, hygiene, stress) (Ring et al., 1992;Bonamonte et al., 2019). Patients suffering from atopic eczema revealed significantly reduced quality of life due to itching, which leads to sleep disturbances (Blome et al., 2016). The severe form of AD had a significant impact on the quality of life in adult patients compared to the mild and moderate types of AD (Chiesa Fuxench et al., 2019). Moreover, AD is a serious socio-economic problem in health care units because of the long treatment duration and financial costs (Carroll et al., 2005). In addition to the long-term and burdensome treatment of AD patients, colonization by Staphylococcus aureus is another serious problem. Staphylococcus aureus is associated with the severity, pathogenesis and exacerbation of AD. INCREASED STAPHYLOCOCCUS AUREUS COLONIZATION RATE FOR AD PATIENTS The phenomenon of S. aureus colonization in AD patients has been known for a long time (Leyden and Marples, 1973;Hauser et al., 1985). Hauser et al. demonstrated higher S. aureus density, S. aureus fraction (SAF index) and total CFU/cm2(CFU–colony forming units) in the lesional skin in AD patients than in the healthy control group (Hauser et al., 1985). In children suffering from AD, S. aureus colonization rate is higher than in the healthy group and affects 57–100% of children (Bunikowski et al., 2000; Arkwright et al., 2001;Lo et al., 2010;Pascolini et al., 2011). More than 40% of AD children are colonized both on the lesional skin and in the anterior nares (Pascolini et al., 2011). In children with AD, the carriage of the S. aureus strains in the anterior nares could be a potential source of recolonization (Patel et al., 2001). Results concerning S. aureus presence from AD children are summarized in Table 1. Regarding S. aureus colonization in adult patients, 54–100% (Breuer et al., 2002;Tomi et al., 2005;Gong et al., 2006;Kim et al., 2009;Na et al., 2012;Rojo et al., 2014;Clausen et al., 2017, 2019) suffering from AD were colonized by this species. S. aureus isolates formed a reservoir in the nose in AD patients. It can be diffused by autotransmission on the skin area (Breuer et al., 2002). The most colonized site is lesional skin (56–96.2%) (Matsui et al., 2000;Park et al., 2016;Totté et al., 2016;Alsterholm et al., 2017), nose (46.1–64.1%) (Na et al., 2012;Park et al., 2016;Totté et al., 2016;Clausen et al., 2017), and non-lesional skin (28–39%) (Matsui et al., 2000;Totté et al., 2016;Clausen et al., 2017). Several studies demonstrated that 65–77.3% (Breuer et al., 2002;Tomi et al., 2005;Na et al., 2012) of AD patients were colonized both in the anterior nares and on the skin, whereas only 10.2% of healthy control subjects were colonized on the skin (Matsui et al., 2000). Alsterholm et al. (2017) found that 55% of the AD patients were persistent carriers of S. aureus. Moreover, persistent S. aureus carriers had a higher SCORAD than intermittent carriers or noncarriers. It turns out that not only the nose but also the skin could be an important reservoir of S. aureus in AD patients (Alsterholm et al., 2017). Frequent recolonization by S. aureus between nose and skin was observed, which can contribute to the severity of AD (Chiu et al., 2009). Results concerning the distribution of S. aureus in adults are summarized in Table 2. High S. aureus colonization rate is observed in both groups, children and adults. Colonization rate increases with the severity of the AD, and it acts as an aggravating factor exacerbating inflammation (Breuer et al., 2002). Also, colonization with S. aureus in AD patients could be a potent risk of various invasive infections, e.g., bacteremia, septic shock, osteomyelitis, necrotizing pneumonia, or septic arthritis (Patel and Jahnke, 2015). MRSA VS. MSSA DISTRIBUTION IN ATOPIC DERMATITIS Among S. aureus isolates, methicillin-resistant S. aureus (MRSA) constitutes an important and significant group that requires particular concern. MRSA is a group of strains that are resistant to multiple β-lactam antibiotics (cephalosporins, carbapenems, monobactams, and penicillins). This phenotype results in limited treatment options, including for skin infections (Rangel and Paller, 2018). It has been demonstrated that among S. aureus strains colonizing AD patients, the percentage of MRSA is 4–13 times higher than in a healthy population (Suh et al., 2008;Lo et al., 2010). Currently, three profiles of MRSA are distinguished: hospital-associated (HA-MRSA), community-associated (CAMRSA), and livestock-associated MRSA (LA-MRSA). Initially, epidemiological investigations indicated that MRSA infections related only to hospitalized patients (HA-MRSA). However, later it turned out that MRSA can also be isolated from infected Frontiers in Microbiology | www.frontiersin.org 2January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 3 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis TABLE 1 | The distribution of S. aureus colonization and toxins production in children with atopic dermatitis. References Examined groups Sites of isolation Colonization staphylococcus aureus Toxins production Bunikowski et al. (2000) Germany Children with AD (n= 74) Healthy control patients (n= 25) Unaffected and eczematous skin lesions Neck Wrist Elbow Erosive eczematous lesions AD patients 60 (81%) were S. aureus positive [including 40 (53%) toxigenic S. aureus strains] Healthy controls 5 (20%) were S. aureus positive [including 1 toxigenic S. aureus strain] AD patients sea: 12, seb: 9, sec: 12, sed:3,tsst-1: 9 Healthy controls sea: 1 Arkwright et al. (2001) United Kingdom Children with AD (n= 28) Eczematous lesions Nares Each of the examined patients was colonized Skin sea: 3 (11%), seb: 1 (4%), sec: 7 (25%), sed: 1 (4%), see: 0, seg&sei: 6 (21%), seh: 0, tsst-1: 3 (11%) Nose sea: 2 (7%), seb: 0, sec: 3 (11%), sed: 1 (4%), see: 0, seg&sei: 5 (17%), seh: 1 (4%), tsst-1: 2 (7%) Lomholt et al. (2005) Denmark Children with AD (n= 11) Anterior nares Axillae Area of active eczema Perineum No data sea: 8 (29%), seb: 1 (4%), sec: 1 (4%), sed: 0 (0%), tsst-1: 0 (0%) Lo et al. (2010) Taiwan Children with AD (n= 133) Children with AD and SSTI (n= 20) Healthy controls (n= 490) The anterior nares Children with AD 67 isolates were positive for S. aureus (23 MRSA and 44 MSSA) Children with AD and SSTI 20 isolates were positive for S. aureus (12 MRSA and 8 MSSA) Healthy controls 170 isolates were positive for S. aureus (44 MRSA and 126 MSSA) Results from molecular characteristics of 79 MRSA isolates from 643 children Children with AD sea: 1 (4%), seb: 20 (87%), sec: 2 (9%), sed:0,seg/sei: 1 (4%), seh: 1 (4%), tsst-1: 2 (9%), Children with AD and SSTI sea: 0, seb: 12 (100%), sec: 0, sed: 0, seg/sei:0,seh: 1 (8%), tsst-1: 0, Healthy controls sea: 3 (7%), seb: 28 (64%), sec: 11 (25%), sed: 1 (2%), seg/sei: 11 (25%), seh:0,tsst-1: 7 (16%) Pascolini et al. (2011) Italy Children with AD (n = 117) Healthy controls (n= 90) Skin lesions Normal skin areas Nares Children with AD 66 patients (57%) - lesional skin and nares: 47 (40.2%) - nares: 19 (16.2%) - uninvolved skin: 4 (3.4%) Healthy children 18 patients (20%) - nares: 18 - uninvolved skin: 0 Enterotoxins 71 positive among 90 S. aureus strains Tsst-1 40 positive among 90 S. aureus strains Park et al. (2013) Korea Infants with AD (n = 188) Children with AD (n= 267) Control group— patients with urticaria (n= 247) Skin lesions (acute and chronic) Infantsacute lesion: 50% (18/36) - chronic lesion: 18.5% (28/151) Childrenacute lesion: 80% (44/55) - chronic lesion: 41.8% (90/215) No data Gilaberte et al. (2015) Spain Children with AD (n= 114) Clinically uninfected lesional skin (antecubital or popliteal areas) Nares Skin: 32/113 (28.3%) Nares: 20/85 (23.5%) All S. aureus strains were MSSA except one MRSA isolated from the skin Skin and nasal isolates seb: 1 (2.5%), sec: 2 (5%), tsst-1: 22 (55%) Skin isolates seb: 0, sec: 2 (7.7%), tsst-1: 13 (50%) Abad et al. (2019) Brazil Children with AD (n= 117)—2 months–14 years old Nasal swabs 97/117 of patients (82.90%) were colonized with S. aureus - 26/97 (22.22%) MRSA - 71/97 (60.68%) MSSA No data Frontiers in Microbiology | www.frontiersin.org 3January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 4 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis TABLE 2 | The distribution of S. aureus colonization and toxins production in adults with atopic dermatitis. References Examined groups Sites of isolation Colonization of staphylococcus aureus Toxins production Zollner et al. (2000) Germany AD patients (n= 33) Atopic controls (n= 21) Healthy controls (n= 50) AD patients: mucous membranes (nose and throat), involved skin Healthy controls: healthy skin of the elbows AD patients: 23/33 (69.70%) Atopic controls: 9/21 (42.86%) Healthy controls: 15/50 (30%) AD patients 13/23 (57%) isolates produced SEs seb (5/13, 38%), sec (1/13, 8%), sed (1/13, 8%), tsst-1 (3/13, 23%) Atopic controls 3/9 (33%) isolates produced SEs sea (2/3, 66%), seb (1/3, 33%), tsst-1 (1/3, 33%) Healthy controls 5/15 (33%) isolates produced SEs sea (1/5, 20%), seb (1/5, 20%), tsst-1 (3/5, 60%) Breuer et al. (2002) Germany Patients with AD–adults (n= 66) Skin Anterior nares 62 of the 66 patients (94%) - skin(+), nose(+): 51 (77.3%) - skin(+), nose(−): 7 (10.6%) - skin(−). nose(+): 4 (6.1%) - skin(−), nose(−): 4 (6.1%) Cutaneous and nasal isolates from 32 patients were included in the study. 10 (31%) of the patients were colonized with toxigenic S. aureus Skin sea = sed >seb >sec =tsst-1 Nose sed >seb >sea =sec tsst-1 was not detected Schlievert et al. (2008) United States Group 1 isolates Patients with steroid-resistant atopic dermatitis (n= 78) Group 2 isolates Healthy women vaginas (n= 30) Group 3 isolates Patients with atopic dermatitis (n= 22) Group 1 isolates: 4 the most affected eczematous lesions No data Group 1 sea: 37 (47%), seb: 33 (42%), sec: 23 (29%), sed: 38 (49%), see: 33 (42%), sei: 38 (49%), tsst-1: 27 (35%) Group 2 sea: 8 (27%), seb: 3 (10%), sec: 9 (30%), sed: 4 (13%), see: 6 (20%), sei: 10 (33%), tsst-1: 12 (40%) Group 3 sea: 4 (18%), seb: 2 (9%), sec: 2 (9%), sed: 1 (4.5%), see: 6 (27%), sei: 10 (45%), tsst-1: 11 (50%) Kim et al. (2009) Korea Adolescent or adult patients with AD (n= 42) The eczematous lesions: Lateral neck Forearm Abdomen Popliteal area 35 of the 42 patients (83.3%) sea: 35 (97.2%), seb: 1 (2.8%), sec:0,sed: 5 (13.9%), see: 0, tsst-1: 35 (97.2%) Park et al. (2013) Korea Adults with AD (n= 232) Control group—patients with urticaria (n= 247) Skin lesions (acute and chronic) Adults - acute lesions: 87.5% (35/40) - chronic lesions: 48.9% (93/190) No data Alsterholm et al. (2017) Sweden Patients with AD (n= 21) Lesional skin Anterior nares Perineum Tonsils Non-lesional skin Lesional skin: 57–65% Non-lesional skin: 53–71% Anterior nares: 53–67% Tonsils: 24–30% Perineum: 32–55% No data Clausen et al. (2019) Denmark AD patients (n= 63) Lesional skin Non-lesional skin Nose 34 of patients (54%): - lesional skin: 33% - non-lesional skin: 10% - nose: 41% No data Frontiers in Microbiology | www.frontiersin.org 4January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 5 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis people that have not been exposed to healthcare-related risks (CA-MRSA). The first outbreak of CA-MRSA was described in 1981 in the United States (Saravolatz et al., 1982) and nowadays is associated with skin and soft tissue infections (King et al., 2006;Chung et al., 2008). The skin of patients with AD could be a favorable reservoir for CA-MRSA. In the United States, 18.3% of AD patients are colonized with CA-MRSA (Chung et al., 2008). Colonization with MRSA constitutes the best-known risk factor for developing infection and MRSA can be easily transferred via direct skin-to-skin contact in the public settings, e.g., gyms, thus spreading the bacteria further. Reported in recent years, LA-MRSA is of animal origin, but it has also been detected in humans (van Cleef et al., 2011). It typically causes skin and soft tissue infections (SSTI) as well as more severe infections, similar to HAand CA-MRSA. Some epidemiological data on the prevalence of LA-MRSA skin and soft tissue infections account for 15% of all MRSA SSTI infections in the community (Butaye et al., 2016). However, similar data in the AD population are not currently available. Nasal carriage of S. aureus plays a vital role in the epidemiology and pathogenesis of AD disease. Nevertheless, the distribution of MRSA strains among AD patients is still divergent in the worldwide population. Among S. aureus-positive swabs from the anterior nares of AD patients, 34% were MRSA, in contrast to 26% from healthy children (Lo et al., 2010). In another study carried out in Brazilian AD children, 22.22% of S. aureus isolated strains were MRSA. On the other hand, when Korean AD children skin lesions were screened, 18.4% S. aureus strains were MRSA. Finally, among the isolates from AD children from Italy, only 7.9% were MRSA (12.8% from the skin lesion and 4.5% from the nose) (Chung et al., 2008; Pascolini et al., 2011). Moreover, they indicated that children with AD who had contact with wounds and pus at home or with persons colonized by MRSA had an increased risk of acquisition MRSA. In the case of adults with AD, the overall distribution of MRSA isolates seems to be much lower (Kim et al., 2009) or even absent (Rojo et al., 2014), as compared to the children in AD population. Studies mentioned above indicate that the distribution of MRSA isolates among AD patients reflects an increased prevalence of MRSA in the AD population as compared to healthy ones, in particular in children. Notably, among patients expressing a severe type of AD, a higher risk of MRSA acquisition with time was reported in comparison to patients with a mild or moderate AD type (Abad et al., 2019). FACTORS PREDISPOSING TO THE S. AUREUS COLONIZATION One of the main factors predisposing to the S. aureus colonization are changes in the composition of lipids and fatty acids in the skin. In the epidermis (especially in the stratum corneum) significantly lower level of ceramides and higher amount of cholesterol was observed (Figure 2;Murata et al., 1996;Di Nardo et al., 1998). The reduction of skin lipids level could explain the role of these components in maintaining the hydration of the skin (Coderch et al., 2003). Similarly, ceramides and sphingosine levels are reduced in the stratum corneum of AD patients, which may favor S. aureus colonization. It was shown that sphingosine reveals the antimicrobial effect against S. aureus (Arikawa et al., 2002). Furthermore, S. aureus that colonized patients with AD produced an enzyme—ceramidase (Ohnishi et al., 1999). Since ceramides play a crucial role in the water-retaining in the stratum corneum, ceramidases action lead to the deficiency of ceramides molecules, which is associated with increasing trans-epidermal water loss and characteristic dry, cracked skin in patients with AD (Arikawa et al., 2002). The level of antimicrobial peptides (AMPs) and host defense peptides (HDPs), produced by keratinocytes such as dermicidin, human β-defensins and cathelicidin–LL-37 are markedly reduced in AD skin, which also conduces to S. aureus colonization and infection (Ong et al., 2002;Roll et al., 2004). These peptides efficiently inhibit S. aureus growth (Niyonsaba et al., 2017). Th2 cytokines IL-4, IL-13, and IL-31, which are overexpressed in AD patients, inhibited the expression of the human β-defensins genes (hBD-2 and hBD-3). It is probably one of the factors that contribute to the proliferation of S. aureus, disturbance of microbiota composition and implication in the AD pathogenesis (Kanda and Watanabe, 2012). Filaggrin (FLG) is an epidermal protein which is a part of the stratum corneum, the main barrier of the skin. Filaggrin is responsible for hydration, maintaining epidermal homeostasis, creating chemical, and structural barrier function (O’Regan and Irvine, 2008). The primary function is bonding keratin cytoskeleton in the process of keratinocytes maturation in the skin layer (Candi et al., 2005;Brown and McLean, 2012). Filaggrin can act as a scaffold for the connection of the lipids layers (O’Regan et al., 2008). As a result of filaggrin breakdown, pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA) are formed, which are the composition of natural moisturizing factor (NMF) (Rawlings et al., 1994;O’Regan et al., 2008). This factor plays a crucial role in maintaining hydration of the stratum corneum and the appropriate pH of the skin (Rawlings et al., 1994;O’Regan et al., 2008). Nowadays, most studies proved that filaggrin loss-of-function mutations play an important role in the aggravation process in patients with AD (Brown and McLean, 2012). Reduced levels of filaggrin cause skin inflammation, resulting from the increasing penetration of allergens or irritants (Gruber et al., 2011). Furthermore, the levels of filaggrin and NMF are significantly decreased in AD patients (Brown and McLean, 2012). Also, PCA and UCA, filaggrin breakdown products have been in vitro shown to impact S. aureus cell density and growth rate (Miajlovic et al., 2010). Notably, in patients with a mutation in the filaggrin gene (FLG) increased S. aureus colonization was showed as compared to wild-type patients (Clausen et al., 2017). In the skin, pH level plays a key role in maintaining the proper barrier function in the epidermis, protection against pathogens and control of the process of desquamation. The pH level of healthy skin is slightly acidic (4.0–6.0). Fatty acids–products of the phospholipid hydrolysis in sebum and sweat, maintain the low pH level (Chan and Mauro, 2011). There is an association Frontiers in Microbiology | www.frontiersin.org 5January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 6 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis FIGURE 2 | Factors predisposing to the S. aureus colonization. between the lower pH level and the reduced expression of proteins, in particular, those involved in adherence to the skin by S. aureus (e.g., protein A, clumping factor B, fibronectin-binding protein A) (Leung, 2013). Therefore, changes in the pH level toward more alkaline are one of the factors, facilitating S. aureus colonization and growth in AD patients (O’Regan and Irvine, 2008;Proksch et al., 2008;Clausen et al., 2019). The pH 7.0– 8.0 has been shown optimal for S. aureus adhesion to human keratinocytes (Mempel et al., 1998). NO MAJOR S. AUREUS CLONES COULD BE ASSIGNED TO ISOLATES FROM AD PATIENTS Due to the frequent occurrence of S. aureus in patients with AD, as well as the growing number of scientific reports on the mechanisms of immune response induction by specific virulence factors, a natural question arises whether there are selected S. aureus clones/types associated with the disease. A “gold standard” to determine the clonality of S. aureus strains, especially MRSA, is PFGE (Pulsed Field Gel Electrophoresis) (He et al., 2014). A specific “DNA fingerprint” for an individual clone is assigned to a specific pulsotype (e.g., A, B, C) (Golding et al., 2015). PFGE genotyping of S. aureus indicated that among the isolates from AD children, the most common pulsotype was B (48%). In contrast, pulsotype A was the most frequent in the healthy control group (64%) (Lo et al., 2010). However, Lomholt et al. (2005) indicated that 28 various S. aureus PFGE pulsotypes could be reported for AD patients. With the application of MLST (multi-locus sequence typing), that is another useful method of microbial genotyping, Kim et al. (2009) revealed that sequence types ST188, ST1, ST5, and ST513 were the most frequently identified in the studied adolescent or adult patients with AD (19.4, 13.9, 11.1, and 11.1%, respectively). These data demonstrated the absence of prevailed genotype. Additionally, most of the detected lineages (especially ST188 and ST1) were community-acquired strains in contrast to only a single ST5, which in Korea is associated with hospitalacquired strains. Clausen et al. focused on the distribution of clonal complexes (CCs) determined based on spa typing among strains isolated from AD patients. As much as 92% of S. aureus isolates demonstrated identical spa types in three studied sites (nose, lesional, non-lesional skin). The most frequent spa types were t008, t084, t127, and t948 (Clausen et al., 2017). Different results were obtained by Kim et al. (2009), who identified t189 (19.4%) as the most frequent type, followed by t127 (13.9%), t164 (11.1%), and t304 (8.1%). These results confirm the observation on the heterogeneity of S. aureus strains isolated from AD patients. Applying yet another typing method, namely, CC typing, Yeung et al. (2011) proved that in AD patients (adults and children), the most common clonal complex was CC45 (34 of S. aureus isolates out of 160), CC5 (23 isolates), CC15 (22 isolates), CC1 (21 isolates), CC30 (11 isolates), and CC398 (8 isolates). In another study by Rojo et al. (2014) two groups of patients were included as follows: AD patients (n= 32) and patients who suffered from other atopic diseases (asthma, allergic rhinitis or food allergy, n= 31). Among AD patients, the most frequent CC was CC5 (31.2%), CC15 (18.7%), CC30 (18.7%), and CC45 (15.6%), whereas CC30 mostly prevailed in the control group (48.3%) (Rojo et al., 2014). Also, it was demonstrated that 95% of examined samples from AD patients belonged to the same clonal complex in three sampling sites (nose, lesional and non-lesional skin). Interestingly, the authors observed that CC1 was identified more frequently in patients with filaggrin mutations (Clausen et al., 2017). Similarly, Harkins et al. found in the inflamed skin of children with AD that the most prevalent clonal complex was CC1 (20%), whereas CC30 (33%), and CC45 (22%) were predominantly detected in the anterior nares of healthy children (Harkins et al., 2018). Temporal variation of CC types in S. aureus was observed in patients with mild to moderate AD where 52% of patients Frontiers in Microbiology | www.frontiersin.org 6January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 7 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis examined during follow up study were colonized by the same CC type. Interestingly, nearly half of the studied patients (48%) demonstrated different CC types during the follow-up study, which correlated with increased SCORAD (Clausen et al., 2019). Genetic variations present in S. aureus has been shown to influence clinical outcome in some essential diseases (Messina et al., 2016). The connection between clonal complex and infections was documented for CC8 associated with sepsis, CC30 associated with endocarditis or CC398 associated with nasal carriage and bone and joint infection (Nienaber et al., 2011;Spaulding et al., 2012;Valour et al., 2014). The distribution of staphylococcal clonal complexes in AD patients that has been analyzed throughout the recent years points for great heterogeneity, and no specific clone/clones prevailed in this group of patients. Moreover, observations proved that populations of S. aureus isolated from AD patients are very clonal, and that characteristic virulence factor variants that have been shown to contribute to AD may occur in different clonal lineages. This further means that this is rather unlikely to characterize specific S. aureus lineages associated with AD and disease severity, at least based on traditional typing methods (Kim et al., 2009;Yeung et al., 2011;Rojo et al., 2014;Clausen et al., 2017). The only example of a correlation between S. aureus genetic background and AD was the one found by Clausen et al., where CC1 clone was the most commonly detected among AD patients (22% of all colonized patients) and significantly more prevalent in filaggrin mutation carriers (Clausen et al., 2018). Nevertheless, considering the above observation and the dynamic evolution of the S. aureus species based on the survival of only those populations that can survive in given conditions (e.g., in a defective atopic skin), the existence of AD-specific genotype(s) cannot be excluded. S. aureus genetic variations that might contribute to a particular clinical outcome (like infection of atopic skin) might be present at different levels: clonal, gene, or at the level of gene polymorphisms. Therefore, detailed knowledge about the bacterial genetic variation is needed to understand better the role of S. aureus in the pathogenesis of AD. A NEW CONCEPT OF STRAIN-SPECIFIC COLONIZATION OF S. AUREUS IN AD Traditional genotyping methods allow the differentiation of staphylococcal isolates from AD patients. These methods, however, have their resolution limitations, which did not allow identification of specific genetic features of AD-derived S. aureus. At the same time, there are functional differences manifested by altered immune responses in the skin between AD S. aureus strains vs. non-AD S. aureus strains. It was observed that only AD-derived S. aureus strains altered T cell response via Langerhans cells (Iwamoto et al., 2017), and only AD-derived strains accumulated in lysosomes and induced IL-1αproduction via Toll-like receptor 9 (Moriwaki et al., 2019). The observed differences have been attributed to surface proteins (Iwamoto et al., 2017;Moriwaki et al., 2019). In line with those reports, S. aureus isolated from AD but not from healthy carriers induced strong inflammation in the mouse model of AD (Byrd et al., 2017). Whole-genome sequencing of AD-derived S. aureus revealed genes coding for proteins associated with infection, carotenoid production, or β-lactam resistance to be associated with AD colonization (Byrd et al., 2017). Analyzing AD microbiome suggests that AD patients may be preferentially colonized by those S. aureus strains that can synthesize tryptophan (Fyhrquist et al., 2019). It was experimentally shown, however, that tryptophan metabolites on atopic skin are significantly reduced, and therefore strains that do not require exogenous tryptophan for growth may be preferred (Yu et al., 2019). The concept of specific S. aureus isolates that have a more significant potential to colonize atopic skin or induce an immune effect in AD patients has developed significantly in recent years. Mainly due to the results of studies linking the production of S. aureus δ-toxin with allergic skin diseases (Nakamura et al., 2013). Staphylococcus aureus once established on the skin, promotes inflammation through multiple pathways. Recent work from several laboratories has advanced our understanding of how the skin colonization of S. aureus promotes inflammatory skin diseases. The general overview of the pathways involved in S. aureus and its virulence factors contribution to AD is presented in Figure 3. It has been documented that S. aureus is able not only to colonize the surface of the skin, but it also penetrates the dermis, where the bacterium can come into direct contact with immune cells and stimulate the production of proinflammatory cytokines (Nakatsuji et al., 2016). S. aureus produces a range of potent virulence factors that appeared to play a crucial role in the inflammation process driven by the bacterium, e.g., PSMs (phenol soluble modulins), proteases (aureolysin, V8 protease, SspA serine protease, ScpA cysteine protease), superantigens (staphylococcal enterotoxin A, B, TSST-1). PSMαhas been shown to induce expression of cytokines in keratinocyte cell lines as well as in a mouse model of AD via lysis of keratinocytes, which led to the release of inflammatory cytokines (Syed et al., 2015). Another PSM representative, namely δ-toxin was identified in abundant amounts in culture supernatants of S. aureus isolated from the skin of AD patients and was shown to be a potent inducer of mast cells degranulation suggesting for the first time a link between S. aureus colonization and allergic skin diseases (Nakamura et al., 2013). In this case, the mechanism of action was different from other PSMs, as δ-toxin (PSMγ) did not cause cell lysis but rather induced signaling pathway leading to increased IgE, IL-4 levels (Figure 3). PSMs are critical for the induction of IL-17 producing cells, namely γδTcells or ILC3 (type 3 lymphoid cells), which are mediators of skin inflammation in response to S. aureus (Nakagawa et al., 2017). Depending on the depth bacteria can reach in the skin–epidermis vs. dermis, different host response can be elicited. Epicutaneous exposure of S. aureus promotes inflammation via IL-36, produced mostly by keratinocytes, whereas intradermal challenge promotes IL-1β induction of inflammation (Liu et al., 2017). The penetration depth has been shown to critically depend on an important group of virulence factors produced by the bacterium, namely serine proteases (Nakatsuji et al., 2016). Frontiers in Microbiology | www.frontiersin.org 7January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 8 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis FIGURE 3 | Pathways involved in S. aureus’ virulence factors contribution to AD. (Created with BioRender). Toll-like receptors (TLRs), recognizing various bacterial antigens (e.g., cell wall components), transduce a signal through MyD88 (Myeloid differentiation primary response gene-88) signaling pathway that leads to activation of NFκB transcription factor and production of proinflammatory cytokines (Kuo et al., 2013). Recently, MyD88-dependent signaling was demonstrated a critical pathway activated in response to staphylococcal virulence factors–PSMα(Liu et al., 2017) and SEB (Faßbender et al., 2017). SEB is one of the best-studied enterotoxins in the context of inflammation in AD patients, next to SEA and TSST-1. However, in recent years, experimental data on other members of this group of virulence factors have emerged, expanding our understanding of the mechanisms linking S. aureus and AD (Aziz et al., 2019; Orfali et al., 2019). A transcriptomic approach to study keratinocyte response to SEB or TSST-1 has been shown to upor downregulate more than 3,000 genes, confirming a previously proposed signaling pathway through CD40 receptor (Schlievert et al., 2020). These phenomena require even more detailed knowledge, but it turns out that S. aureus may play a vital role in the development of AD in a strain-specific manner. The experimental data trying to provide an answer to a question whether S. aureus causes AD or its increased survival on AD skin is a consequence of the disease is only starting to emerge. More and more puzzles add up to a complete picture that may soon allow us to understand better the molecular mechanism of a complex relation between S. aureus and AD (Geoghegan et al., 2018). AN AMBIGUITY OF STAPHYLOCOCCAL ENTEROTOXINS (SEs) IN ATOPIC DERMATITIS From the vast repertoire of S. aureus’ virulence factors, we will focus on a specific group–enterotoxins, which S. aureus produces dozens of varieties. The pyrogenic toxin superantigen (PTSA) family is the group of staphylococcal toxins that includes the following clusters: staphylococcal enterotoxins (SEs), staphylococcal enterotoxinlike toxins (SEls), and toxic shock syndrome toxin (TSST-1). The nomenclature distinguished SEs (SEA, SEB, SEC, SED, SEE) from SEls (SElG, SElH, SElJ, SElK, SElL, SElM, SElN, SElO, SElP, and SElQ) is based on their causing (SEs) or not causing (SEls) emesis in humans (Figure 4;Lina et al., 2004). Staphylococcal enterotoxins (SEs) are known as bacterial virulence factors that contribute to the development of many human diseases, including toxic shock syndrome or food poisoning (Harris et al., 1993;Balaban and Rasooly, 2000;Ortega et al., 2010;Pinchuk et al., 2010). Many authors have indicated a role for SEs in the course of AD by acting as factors aggravating and exacerbating the inflammation of AD skin (Bunikowski et al., 2000;Taskapan and Kumar, 2000;Yarwood et al., 2000;Zollner et al., 2000). Moreover, there are indications for the causative role of SEs in the course of AD. The most common feature of SEs is that they possess superantigenic properties (Spaulding et al., 2013). Superantigens (SAgs) can bind as intact proteins to the T-cell antigen receptor (TCR) and the major histocompatibility complex II Frontiers in Microbiology | www.frontiersin.org 8January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 9 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis FIGURE 4 | Three clusters of staphylococcal toxins. (MHC II) outside their binding site (Fink et al., 1986) thus, stimulating massive proliferation of nonspecific T cells and release of proinflammatory cytokines (Harris et al., 1993; Holtfreter et al., 2006). Because of interest in SEs as an aggravating factor in AD, their distribution in AD-derived S. aureus isolates was a matter of deep interest. The main question researchers asked concerned a potential pattern (universal vs. specific) of SEs presence in ADderived S. aureus. It has been known that 54–71.25% of S. aureus isolates indicated the presence of SE genes among AD patients (Mempel et al., 2003;Nada et al., 2012). Furthermore, a metaanalysis of 95 studies indicated that the rate of toxins producing S. aureus on the lesional skin fluctuated between 31.5 and 80% (Totté et al., 2016), and was higher than in healthy controls. The distribution of SE genes, however, varied from one studied population to another: in Korean population sea and tsst-1 were the most common toxin genes (Kim et al., 2009;Na et al., 2012); in Germany, whereas one study showed that seb (38%) and tsst1(23%) toxin genes were the most prevalent, and sea was not detected (Zollner et al., 2000), other revealed that sea and sed were most commonly detected (Breuer et al., 2002). All SEs production patterns from adult AD patients are summarized in Table 2. In the studies of Taiwanese children with AD, the most frequent toxin gene was seb (87%), followed by sec (9%), tsst-1 (9%), sea (4%), seg/sei (4%), and seh (4%). The sed toxin gene was not identified in atopic children, whereas it was predominant in healthy children. It is worth to mention, however, that only the MRSA population was studied (Lo et al., 2010). In England, the most prevalent toxins were sec (25% from the skin; 11% from the nose), seg (21% from the skin; 17% from the nose), and sei (21% from the skin; 17% from the nose). Most cases represented the same strains in the nose and skin (Arkwright et al., 2001). In Spain, hla and hlg/hlgV (26, 100%), hlb (17, 65.5%), lukDE (25, 96.1%), tsst-1 (13, 50%), aur (11, 42.3%), cna (10, 38.5%), eta (4, 15.4%), and sec (2, 7.7%) were the virulence genes detected in cutaneous isolates of children with AD (Gilaberte et al., 2015). The observed variations in SEs distribution patterns in different research and different AD populations indicate geographical dependence. All SEs production patterns from AD children are summarized in Table 1. Interestingly, in some studies based on populations of both children and adults, the most frequently detected genes were not classical toxins found in 38% of AD-derived strains, but enterotoxin gene cluster (egc), which consisted of seg, sei, sek, sem, sen, and seo (Mempel et al., 2003). Studies on the AD cohort from Singapore indicated that the most prevalent SEs were seb (42%), egc (32%), and seh (29%). Interestingly, Chiu et al. proposed that patients with a moderate type of AD were more likely to be colonized by S. aureus possessing staphylococcal enterotoxin B (seb) than patients with a severe type of AD (Chiu et al., 2009). Nevertheless, another distribution pattern of toxins was observed in Portuguese AD patients, where 76% of the examined S. aureus strains were SE-positive, mainly for SEls:sel-m and sel-n (71.4%), followed by sel-o and seg (66.7%) and sea and sel-l were less frequent (29% and 33%, respectively) (Soares et al., 2013). In the Egyptian cohort, the most prevalent gene from the S. aureus strains isolated from the lesional skin of AD patients was seb, followed by sec and tsst-1,sea and sed (Nada et al., 2012). All SEs gene presence patterns from the mixed groups of AD patients are summarized in Table 3. It is not uncommon that AD-derived strains of S. aureus can produce more than a single enterotoxin (Schlievert et al., 2008; Na et al., 2012), and at significantly higher amounts (Schlievert et al., 2008). The overall picture is even more complex when Frontiers in Microbiology | www.frontiersin.org 9January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 16 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis Carroll, C. L., Balkrishnan, R., Feldman, S. R., Fleischer, A. B., and Manuel, J. C. (2005). The burden of atopic dermatitis: impact on the patient, family, and society. Pediatr. Dermatol. 22, 192–199. doi: 10.1111/j.1525-1470.2005.22303.x Chan, A., and Mauro, T. (2011). Acidification in the epidermis and the role of secretory phospholipases. Dermatoendocrinology 3, 84–90. doi: 10.4161/derm. 3.2.15140 Chiesa Fuxench, Z. C., Block, J. K., Boguniewicz, M., Boyle, J., Fonacier, L., Gelfand, J. M., et al. (2019). Atopic dermatitis in America study: a cross-sectional study examining the prevalence and disease burden of atopic dermatitis in the US adult population. J. Invest. Dermatol. 139, 583–590. doi: 10.1016/j.jid.2018.08. 028 Chiu, L. S., Ho, M. S. L., Hsu, L. Y., and Tang, M. B. Y. (2009). Prevalence and molecular characteristics of Staphylococcus aureus isolates colonizing patients with atopic dermatitis and their close contacts in Singapore. Br. J. Dermatol. 160, 965–971. doi: 10.1111/j.1365-2133.2009.09038.x Chung, H. J., Jeon, H. S., Sung, H., Kim, M. N., and Hong, S. J. (2008). Epidemiological characteristics of methicillin-resistant Staphylococcus aureus isolates from children with eczematous atopic dermatitis lesions. J. Clin. Microbiol. 46, 991–995. doi: 10.1128/JCM.00698-07 Cieplik, F., Deng, D., Crielaard, W., Buchalla, W., Hellwig, E., Al-Ahmad, A., et al. (2018). Antimicrobial photodynamic therapy–what we know and what we don’t. Crit. Rev. Microbiol. 44, 571–589. doi: 10.1080/1040841X.2018.1467876 Clausen, M. L., Agner, T., Lilje, B., Edslev, S. M., Johannesen, T. B., and Andersen, P. S. (2018). Association of disease severity with skin microbiome and filaggrin gene mutations in adult atopic dermatitis. JAMA Dermatol. 154, 293–300. doi: 10.1001/jamadermatol.2017.5440 Clausen, M. L., Edslev, S. M., Andersen, P. S., Clemmensen, K., Krogfelt, K. A., and Agner, T. (2017). Staphylococcus aureus colonization in atopic eczema and its association with filaggrin gene mutations. Br. J. Dermatol. 177, 1394–1400. doi: 10.1111/bjd.15470 Clausen, M. L., Edslev, S. M., Nørreslet, L. B., Sørensen, J. A., Andersen, P. S., and Agner, T. (2019). Temporal variation of Staphylococcus aureus clonal complexes in atopic dermatitis: a follow-up study. Br. J. Dermatol. 180, 181–186. doi: 10.1111/bjd.17033 Coderch, L., López, O., De La Maza, A., and Parra, J. L. (2003). Ceramides and skin function. Am. J. Clin. Dermatol. 4, 107–129. doi: 10.2165/00128071-20030402000004 Darsow, U., Lübbe, J., Taïeb, A., Seidenari, S., Wollenberg, A., Calza, A. M., et al. (2005). Position paper on diagnosis and treatment of atopic dermatitis. J. Eur. Acad. Dermatol. Venereol. 19, 286–295. doi: 10.1111/j.1468-3083.2005.01249.x Di Nardo, A., Wertz, P., Giannetti, A., and Seidenari, S. (1998). Ceramide and cholesterol composition of the skin of patients with atopic dermatitis. Acta Derm. Venereol. 78, 27–30. doi: 10.1080/00015559850135788 Eichenfield, L. F., Call, R. S., Forsha, D. W., Fowler, J., Hebert, A. A., Spellman, M., et al. (2017). Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J. Am. Acad. Dermatol. 77, 641.e5–649.e5. doi: 10.1016/j.jaad.2017.06.010 Faßbender, S., Opitz, F. V., Johnen, S., Förster, I., and Weighardt, H. (2017). MyD88 contributes to staphylococcal enterotoxin B-triggered atopic dermatitis-like skin inflammation in Mice. J. Invest. Dermatol. 137, 1802–1804. doi: 10.1016/ j.jid.2017.04.015 Ferreira, S., Guttman-Yassky, E., and Torres, T. (2020). Selective JAK1 inhibitors for the treatment of atopic dermatitis: focus on upadacitinib and abrocitinib. Am. J. Clin. Dermatol. 21, 783–798. doi: 10.1007/s40257-020-00548-6 Fink, P. J., Matis, L. A., McElligott, D. L., Bookman, M., and Hedrick, S. M. (1986). Correlations between T-cell specificity and the structure of the antigen receptor. Nature 321, 219–226. doi: 10.1038/321219a0 Fyhrquist, N., Muirhead, G., Prast-Nielsen, S., Jeanmougin, M., Olah, P., Skoog, T., et al. (2019). Microbe-host interplay in atopic dermatitis and psoriasis. Nat. Commun. 10:4703. doi: 10.1038/s41467-019-12253-y Garritsen, F. M., Brouwer, M. W. D., Limpens, J., and Spuls, P. I. (2014). Photo(chemo)therapy in the management of atopic dermatitis: an updated systematic review with implications for practice and research. Br. J. Dermatol. 170, 501–513. doi: 10.1111/bjd.12645 Geoghegan, J. A., Irvine, A. D., and Foster, T. J. (2018). Staphylococcus aureus and atopic dermatitis: a complex and evolving relationship. Trends Microbiol. 26, 484–497. doi: 10.1016/j.tim.2017.11.008 Gilaberte, Y., Sanmartín, R., Aspiroz, C., Hernandez-Martin, A., Benito, D., SanzPuertolas, P., et al. (2015). Correlation between serum 25-hydroxyvitamin D and virulence genes of staphylococcus aureus isolates colonizing children with atopic dermatitis. Pediatr. Dermatol. 32, 506–513. doi: 10.1111/pde. 12436 Golding, G. R., Campbell, J., Spreitzer, D., and Chui, L. (2015). Pulsed-field gel electrophoresis of Staphylococcus aureus.Methods Mol. Biol. 1301, 85–93. doi: 10.1007/978-1-4939-2599-5_8 Gong, J. Q., Lin, L., Lin, T., Hao, F., Zeng, F. Q., Bi, Z. G., et al. (2006). Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br. J. Dermatol. 155, 680–687. doi: 10.1111/j.13652133.2006.07410.x Grinholc, M., Rodziewicz, A., Forys, K., Rapacka-Zdonczyk, A., Kawiak, A., Domachowska, A., et al. (2015). Fine-tuning recA expression in Staphylococcus aureus for antimicrobial photoinactivation: importance of photo-induced DNA damage in the photoinactivation mechanism. Appl. Microbiol. Biotechnol. 99, 9161–9176. doi: 10.1007/s00253-015-6863-z Gruber, R., Elias, P. M., Crumrine, D., Lin, T.-K., Brandner, J. M., Hachem, J.-P., et al. (2011). Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. Am. J. Pathol. 178, 2252–2263. doi: 10.1016/ j.ajpath.2011.01.053 Hanifin, J. M., Cooper, K. D., Ho, V. C., Kang, S., Krafchik, B. R., Margolis, D. J., et al. (2004). Guidelines of care for atopic dermatitis. J. Am. Acad. Dermatol. 50, 391–404. doi: 10.1016/j.jaad.2003.08.003 Hanifin, J. M., and Rajka, G. (1980). Diagnostic features of atopic dermatitis. Acta Derm. Venereol. Suppl. 92, 44–47. Hanifin, J. M., Thurston, M., Omoto, M., Cherill, R., Tofte, S. J., and Graeber, M. (2001). The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. Exp. Dermatol. 10, 11–18. doi: 10.1034/j.1600-0625.2001. 100102.x Harkins, C. P., Pettigrew, K. A., Oravcová, K., Gardner, J., Hearn, R. M. R., Rice, D., et al. (2018). The microevolution and epidemiology of Staphylococcus aureus colonization during atopic eczema disease flare. J. Invest. Dermatol. 138, 336–343. doi: 10.1016/j.jid.2017.09.023 Harris, T. O., Grossman, D., Kappler, J. W., Marrack, P., Rich, R. R., and Betley, M. J. (1993). Lack of complete correlation between emetic and T-cellstimulatory activities of staphylococcal enterotoxins. Infect. Immun. 61, 3175– 3183. doi: 10.1128/IAI.61.8.3175-3183.1993 Hauser, C., Wuethrich, B., Matter, L., Wilhelm, J. A., Sonnabend, W., and Schopfer, K. (1985). Staphylococcus aureus skin colonization in atopic dermatitis patients. Dermatologica 170, 35–39. doi: 10.1159/000249493 He, Y., Xie, Y., and Reed, S. (2014). Pulsed-field gel electrophoresis typing of Staphylococcus aureus isolates. Methods Mol. Biol. 1085, 103–111. doi: 10.1007/ 978-1-62703-664-1_6 Hendricks, A. J., Mills, B. W., and Shi, V. Y. (2019). Skin bacterial transplant in atopic dermatitis: knowns, unknowns and emerging trends. J. Dermatol. Sci. 95, 56–61. doi: 10.1016/j.jdermsci.2019.07.001 Holtfreter, S., Roschack, K., Eichler, P., Eske, K., Holtfreter, B., Kohler, C., et al. (2006). Staphylococcus aureus carriers neutralize superantigens by antibodies specific for their colonizing strain: a potential explanation for their improved prognosis in severe sepsis. J. Infect. Dis. 193, 1275–1278. doi: 10.1086/503048 Hon, K. L., Tsang, Y. C. K., Lee, V. W. Y., Pong, N. H., Ha, G., Lee, S. T., et al. (2016). Efficacy of sodium hypochlorite (bleach) baths to reduce Staphylococcus aureus colonization in childhood onset moderate-to-severe eczema: a randomized, placebo-controlled cross-over trial. J. Dermatolog. Treat. 27, 156–162. doi: 10. 3109/09546634.2015.1067669 Housman, T. S., Patel, M. J., Camacho, F., Feldman, S. R., Fleischer, A. B., and Balkrishnan, R. (2002). Use of the self-administered eczema area and severity index by parent caregivers: results of a validation study. Br. J. Dermatol. 147, 1192–1198. doi: 10.1046/j.1365-2133.2002.05031.x Hung, S.-H., Lin, Y.-T., Chu, C.-Y., Lee, C.-C., Liang, T.-C., Yang, Y.-H., et al. (2007). Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics. Ann. Allergy. Asthma Immunol. 98, 51–56. doi: 10.1016/S1081-1206(10)60859-9 Iwamoto, K., Moriwaki, M., Niitsu, Y., Saino, M., Takahagi, S., Hisatsune, J., et al. (2017). Staphylococcus aureus from atopic dermatitis skin alters cytokine Frontiers in Microbiology | www.frontiersin.org 16 January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 17 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis production triggered by monocyte-derived Langerhans cell. J. Dermatol. Sci. 88, 271–279. doi: 10.1016/j.jdermsci.2017.08.001 Kanda, N., and Watanabe, S. (2012). Increased serum human β-defensin-2 levels in atopic dermatitis: relationship to IL-22 and oncostatin M. Immunobiology 217, 436–445. doi: 10.1016/j.imbio.2011.10.010 Kim, D.-W., Park, J.-Y., Park, K.-D., Kim, T.-H., Lee, W.-J., Lee, S.-J., et al. (2009). Are there predominant strains and toxins of Staphylococcus aureus in atopic dermatitis patients? Genotypic characterization and toxin determination of S. aureus isolated in adolescent and adult patients with atopic dermatitis. J. Dermatol. 36, 75–81. doi: 10.1111/j.1346-8138.2009.00592.x King, M. D., Humphrey, B. J., Wang, Y. F., Kourbatova, E. V., Ray, S. M., and Blumberg, H. M. (2006). Emergence of community-acquired methicillinresistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections. Ann. Intern. Med. 144, 309–317. doi: 10.7326/00034819-144-5-200603070-00005 Kremer, N., Sherman, S., Lapidoth, M., Enk, C. D., Leshem, Y. A., Mimouni, T., et al. (2020). Self-administered daylight-activated photodynamic therapy for the treatment of hand eczema: a prospective proof-of-concept study. Dermatol. Ther. e14329. doi: 10.1111/dth.14329 Kunz, B., Oranje, A. P., Labréze, L., Stabler, J. F., Ring, J., and Taïeb, A. (1997). Clinical validation and guidelines for the scorad index: consensus report of the european task force on atopic dermatitis. Dermatology 195, 10–19. doi: 10.1159/000245677 Kuo, I. H., Yoshida, T., De Benedetto, A., and Beck, L. A. (2013). The cutaneous innate immune response in patients with atopic dermatitis. J. Allergy Clin. Immunol. 131, 266–278. doi: 10.1016/j.jaci.2012.12.1563 Leung, D. Y., Harbeck, R., Bina, P., Reiser, R. F., Yang, E., Norris, D. A., et al. (1993). Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens. J. Clin. Invest. 92, 1374–1380. doi: 10.1172/JCI116711 Leung, D. Y. M. (2013). New Insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol. Int. 62, 151–161. doi: 10.2332/allergolint. 13-RAI-0564 Leyden, J. J., and Marples, R. R. (1973). Ecologic principles and antibiotic therapy in chronic dermatoses. Arch. Dermatol. 107, 208–211. doi: 10.1001/archderm. 1973.01620170020006 Lina, G., Bohach, G. A., Nair, S. P., Hiramatsu, K., Jouvin-Marche, E., and Mariuzza, R. (2004). Standard nomenclature for the superantigens expressed by Staphylococcus.J. Infect. Dis. 189, 2334–2336. doi: 10.1086/420852 Liu, H., Archer, N. K., Dillen, C. A., Wang, Y., Ashbaugh, A. G., Ortines, R. V., et al. (2017). Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-Mediated T cell responses. Cell Host Microbe 22, 653.e5–666.e5. doi: 10.1016/j.chom.2017.10.006 Lo, W. T., Wang, S. R., Tseng, M. H., Huang, C. F., Chen, S. J., and Wang, C. C. (2010). Comparative molecular analysis of meticillin-resistant Staphylococcus aureus isolates from children with atopic dermatitis and healthy subjects in Taiwan. Br. J. Dermatol. 162, 1110–1116. doi: 10.1111/j.1365-2133.2010.09 679.x Lomholt, H., Andersen, K. E., and Kilian, M. (2005). Staphylococcus aureus clonal dynamics and virulence factors in children with atopic dermatitis. J. Invest. Dermatol. 125, 977–982. doi: 10.1111/j.0022-202X.2005.23 916.x Majewski, S., Bhattacharya, T., Asztalos, M., Bohaty, B., Durham, K. C., West, D. P., et al. (2019). Sodium hypochlorite body wash in the management of Staphylococcus aureus–colonized moderate-to-severe atopic dermatitis in infants, children, and adolescents. Pediatr. Dermatol. 36, 442–447. doi: 10.1111/ pde.13842 Matsui, K., Nishikawa, A., Suto, H., Tsuboi, R., and Ogawa, H. (2000). Comparative study of Staphylococcus aureus isolated from lesional and non-lesional skin of atopic dermatitis patients. Microbiol. Immunol. 44, 945–947. doi: 10.1111/ j.1348-0421.2000.tb02587.x Mempel, M., Lina, G., Hojka, M., Schnopp, C., Seidl, H.-P., Schäfer, T., et al. (2003). High prevalence of superantigens associated with the egc locus in Staphylococcus aureus isolates from patients with atopic eczema. Eur. J. Clin. Microbiol. Infect. Dis. 22, 306–309. doi: 10.1007/s10096-0030928-0 Mempel, M., Schmidt, T., Weidinger, S., Schnopp, C., Ring, J., Abeck, D., et al. (1998). Role of Staphylococcus aureus surface-associated proteins in the attachment to cultured HaCaT keratinocytes in a new adhesion assay. J. Invest. Dermatol. 111, 452–456. doi: 10.1046/j.1523-1747.1998.00293.x Merriman, J. A., Mueller, E. A., Cahill, M. P., Beck, L. A., Paller, A. S., Hanifin, J. M., et al. (2016). Temporal and racial differences associated with atopic dermatitis Staphylococcus aureus and encoded virulence factors. mSphere 1:e00295-16. doi: 10.1128/mSphere.00295-16 Messina, J. A., Thaden, J. T., Sharma-Kuinkel, B. K., and Fowler, V. G. (2016). Impact of bacterial and human genetic variation on Staphylococcus aureus infections. PLoS Pathog. 12:e1005330. doi: 10.1371/journal.ppat.1005330 Miajlovic, H., Fallon, P. G., Irvine, A. D., and Foster, T. J. (2010). Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus.J. Allergy Clin. Immunol. 126, 1184.e3–1190.e3. doi: 10.1016/j.jaci.2010. 09.015 Moriwaki, M., Iwamoto, K., Niitsu, Y., Matsushima, A., Yanase, Y., Hisatsune, J., et al. (2019). Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL-1αsecretion via TLR9. Allergy 74, 560–571. doi: 10.1111/all.13622 Murata, Y., Ogata, J., Higaki, Y., Kawashima, M., Yada, Y., Higuchi, K., et al. (1996). Abnormal expression of sphingomyelin acylase in atopic dermatitis: an etiologic factor for ceramide deficiency? J. Invest. Dermatol. 106, 1242–1249. doi: 10.1111/1523-1747.ep12348937 Myles, I. A., Earland, N. J., Anderson, E. D., Moore, I. N., Kieh, M. D., Williams, K. W., et al. (2018). First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI Insight. 3:e120608. doi: 10.1172/ jci.insight.120608 Na, S.-Y., Roh, J.-Y., Kim, J.-M., Tamang, M. D., and Lee, J.-R. (2012). Analysis of colonization and genotyping of the exotoxins of Staphylococcus aureus in patients with atopic dermatitis. Ann. Dermatol. 24:413. doi: 10.5021/ad.2012. 24.4.413 Nada, H. A., Gomaa, N. I. M., Elakhras, A., Wasfy, R., and Baker, R. A. (2012). Skin colonization by superantigen-producing Staphylococcus aureus in Egyptian patients with atopic dermatitis and its relation to disease severity and serum interleukin-4 level. Int. J. Infect. Dis. 16, e29–e33. doi: 10.1016/j.ijid.2011.09.014 Nakagawa, S., Matsumoto, M., Katayama, Y., Oguma, R., Wakabayashi, S., Nygaard, T., et al. (2017). Staphylococcus aureus virulent PSMαpeptides induce keratinocyte alarmin release to orchestrate IL-17-dependent skin inflammation. Cell Host Microbe 22, 667.e5–677.e5. doi: 10.1016/j.chom.2017.10.008 Nakamura, Y., Oscherwitz, J., Cease, K. B., Chan, S. M., Muñoz-Planillo, R., Hasegawa, M., et al. (2013). Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503, 397–401. doi: 10.1038/nature12655 Nakatsuji, T., Chen, T. H., Narala, S., Chun, K. A., Two, A. M., Yun, T., et al. (2017). Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci. Transl. Med. 9:eaah4680. doi: 10.1126/scitranslmed.aah4680 Nakatsuji, T., Chen, T. H., Two, A. M., Chun, K. A., Narala, S., Geha, R. S., et al. (2016). Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression. J. Invest. Dermatol. 136, 2192–2200. doi: 10.1016/j.jid.2016.05.127 Nakatsuji, T., Yun, T., Butcher, A., Hayashi, A., Chun, K., Shafiq, F., et al. (2018). 426 Clinical improvement in atopic dermatitis following autologous application of microbiome therapy targeting Staphylococcus aureus.J. Invest. Dermatol. 138:S72. doi: 10.1016/j.jid.2018.03.433 Nakonieczna, J., Wozniak, A., Pieranski, M., Rapacka-Zdonczyk, A., Ogonowska, P., and Grinholc, M. (2019). Photoinactivation of ESKAPE pathogens: overview of novel therapeutic strategy. Future Med. Chem. 11, 443–461. doi: 10.4155/ fmc-2018-0329 Nienaber, J. J. C., Sharma Kuinkel, B. K., Clarke-Pearson, M., Lamlertthon, S., Park, L., Rude, T. H., et al. (2011). Methicillin-susceptible Staphylococcus aureus endocarditis isolates are associated with clonal complex 30 genotype and a distinct repertoire of enterotoxins and adhesins. J. Infect. Dis. 204, 704–713. doi: 10.1093/infdis/jir389 Niyonsaba, F., Kiatsurayanon, C., Chieosilapatham, P., and Ogawa, H. (2017). Friends or foes? Host defense (antimicrobial) peptides and proteins in human skin diseases. Exp. Dermatol. 26, 989–998. doi: 10.1111/exd.13314 Nomura, I., Tanaka, K., Tomita, H., Katsunuma, T., Ohya, Y., Ikeda, N., et al. (1999). Evaluation of the staphylococcal exotoxins and their specific IgE in childhood atopic dermatitis. J. Allergy Clin. Immunol. 104, 441–446. doi: 10. 1016/S0091-6749(99)70390-8 Frontiers in Microbiology | www.frontiersin.org 17 January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 18 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis Nowicki, R., Trzeciak, M., Wilkowska, A., Sokołowska-Wojdyło, M., ŁugowskaUmer, H., Bara´ nska-Rybak, W., et al. (2015). Atopic dermatitis: current treatment guidelines. Statement of the experts of the dermatological section, polish society of allergology, and the allergology section, polish society of dermatology. Post. Dermatol. Alergol. 32, 239–249. doi: 10.5114/pdia.2015. 53319 Nutten, S. (2015). Atopic dermatitis: global epidemiology and risk factors. Ann. Nutr. Metab. 66, 8–16. doi: 10.1159/000370220 Ohnishi, Y., Okino, N., Ito, M., and Imayama, S. (1999). Ceramidase activity in bacterial skin flora as a possible cause of ceramide deficiency in atopic dermatitis. Clin. Diagn. Lab. Immunol. 6, 101–104. Ong, P. Y., Ohtake, T., Brandt, C., Strickland, I., Boguniewicz, M., Ganz, T., et al. (2002). Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160. doi: 10.1056/nejmoa021481 O’Regan, G. M., and Irvine, A. D. (2008). The role of filaggrin loss-of-function mutations in atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 8, 406–410. doi: 10.1097/ACI.0b013e32830e6fb2 O’Regan, G. M., Sandilands, A., McLean, W. H. I., and Irvine, A. D. (2008). Filaggrin in atopic dermatitis. J. Allergy Clin. Immunol. 122, 689–693. doi: 10.1016/j.jaci.2008.08.002 Orfali, R. L., Yoshikawa, F. S. Y., da Oliveira, L. M. S., Pereira, N. Z., de Lima, J. F., Ramos, Y. ÁL., et al. (2019). Staphylococcal enterotoxins modulate the effector CD4+T cell response by reshaping the gene expression profile in adults with atopic dermatitis. Sci. Rep. 9:13082. doi: 10.1038/s41598-019-49 421-5 Ortega, E., Abriouel, H., Lucas, R., and Gálvez, A. (2010). Multiple roles of Staphylococcus aureus enterotoxins: pathogenicity, superantigenic activity, and correlation to antibiotic resistance. Toxins 2, 2117–2131. doi: 10.3390/ toxins2082117 Park, H. Y., Kim, C. R., Huh, I. S., Jung, M. Y., Seo, E. Y., Park, J. H., et al. (2013). Staphylococcus aureus colonization in acute and chronic skin lesions of patients with atopic dermatitis. Ann. Dermatol. 25, 410–416. doi: 10.5021/ad.2013.25.4. 410 Park, J. M., Jo, J. H., Jin, H., Ko, H. C., Kim, M. B., Kim, J. M., et al. (2016). Change in antimicrobial susceptibility of skin-colonizing Staphylococcus aureus in Korean patients with atopic dermatitis during ten-year period. Ann. Dermatol. 28, 470–478. doi: 10.5021/ad.2016.28.4.470 Pascolini, C., Sinagra, J., Pecetta, S., Bordignon, V., De Santis, A., Cilli, L., et al. (2011). Molecular and immunological characterization of Staphylococcus aureus in pediatric atopic dermatitis: implications for prophylaxis and clinical management. Clin. Dev. Immunol. 2011, 1–7. doi: 10.1155/2011/718708 Patel, D., and Jahnke, M. N. (2015). Serious complications from Staphylococcal aureus in atopic dermatitis. Pediatr. Dermatol. 32, 792–796. doi: 10.1111/pde. 12665 Patel, G. K., Wyatt, H., Kubiak, E. M., Clark, S. M., and Mills, C. M. (2001). Staphylococcus aureus colonization of children with atopic eczema and their parents [2]. Acta Derm. Venereol. 81, 366–367. doi: 10.1080/ 000155501317140124 Pérez-Laguna, V., García-Luque, I., Ballesta, S., Pérez-Artiaga, L., Lampaya-Pérez, V., Samper, S., et al. (2018). Antimicrobial photodynamic activity of Rose Bengal, alone or in combination with gentamicin, against planktonic and biofilm Staphylococcus aureus. Photodiagn. Photodyn. Ther. 21, 211–216. doi: 10.1016/j.pdpdt.2017.11.012 Pérez-Laguna, V., Pérez-Artiaga, L., Lampaya-Pérez, V., García-Luque, I., Ballesta, S., Nonell, S., et al. (2017). Bactericidal effect of photodynamic therapy, alone or in combination with mupirocin or linezolid, on Staphylococcus aureus.Front. Microbiol. 8:1002. doi: 10.3389/fmicb.2017.01002 Pinchuk, I. V., Beswick, E. J., and Reyes, V. E. (2010). Staphylococcal enterotoxins. Toxins 2, 2177–2197. doi: 10.3390/toxins2082177 Pozzi, G., and Asero, R. (2010). Skin photodynamic therapy in severe localized atopic dermatitis: a case report. Br. J. Dermatol. 163, 430–431. doi: 10.1111/j. 1365-2133.2010.09823.x Proksch, E., Brandner, J. M., and Jensen, J. M. (2008). The skin: an indispensable barrier. Exp. Dermatol. 17, 1063–1072. doi: 10.1111/j.1600-0625.2008.00786.x Queirós, C., Garrido, P. M., Maia Silva, J., and Filipe, P. (2020). Photodynamic therapy in dermatology: beyond current indications. Dermatol. Ther. [Epub ahead of print]. doi: 10.1111/dth.13997 Rangel, S. M., and Paller, A. S. (2018). Bacterial colonization, overgrowth, and superinfection in atopic dermatitis. Clin. Dermatol. 36, 641–647. doi: 10.1016/j. clindermatol.2018.05.005 Rawlings, A. V., Scott, I. R., Harding, C. R., and Bowser, P. A. (1994). Stratum corneum moisturization at the molecular level. J. Invest. Dermatol. 124, 1099– 1110. doi: 10.1111/1523-1747.ep12398620 Ring, J., Abeck, D., and Neuber, K. (1992). Atopic eczema: role of microorganisms on the skin surface. Allergy 47, 265–269. doi: 10.1111/j.1398-9995.1992. tb02051.x Rodenbeck, D. L., Silverberg, J. I., and Silverberg, N. B. (2016). Phototherapy for atopic dermatitis. Clin. Dermatol. 34, 607–613. doi: 10.1016/j.clindermatol. 2016.05.011 Rojo, A., Aguinaga, A., Monecke, S., Yuste, J. R., Gastaminza, G., and España, A. (2014). Staphylococcus aureus genomic pattern and atopic dermatitis: may factors other than superantigens be involved? Eur. J. Clin. Microbiol. Infect. Dis. 33, 651–658. doi: 10.1007/s10096-013-2000-z Roll, A., Cozzio, A., Fischer, B., and Schmid-Grendelmeier, P. (2004). Microbial colonization and atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 4, 373–378. doi: 10.1097/00130832-200410000-00008 Rustin, M. H. A. (2007). The safety of tacrolimus ointment for the treatment of atopic dermatitis: a review. Br. J. Dermatol. 157, 861–873. doi: 10.1111/j.13652133.2007.08177.x Saravolatz, L. D., Markowitz, N., Arking, L., Pohlod, D., and Fisher, E. (1982). Methicillin-resistant Staphylococcus aureus. epidemiologic observations during a community-acquired outbreak. Ann. Intern. Med. 96, 11–16. doi: 10.7326/ 0003-4819-96-1-11 Schlievert, P. M., Case, L. C., Strandberg, K. L., Abrams, B. B., and Leung, D. Y. M. (2008). Superantigen profile of Staphylococcus aureus isolates from patients with steroid-resistant atopic dermatitis. Clin. Infect. Dis. 46, 1562–1567. doi: 10.1086/586746 Schlievert, P. M., Gourronc, F. A., Leung, D. Y. M., and Klingelhutz, A. J. (2020). Human keratinocyte response to superantigens. mSphere 5:e00803-20. doi: 10. 1128/mSphere.00803-20 Schwartz, D. M., Kanno, Y., Villarino, A., Ward, M., Gadina, M., and O’Shea, J. J. (2017). JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 16, 843–862. doi: 10.1038/nrd.2017.201 Silverberg, J. I. (2017). Public health burden and epidemiology of atopic dermatitis. Dermatol. Clin. 35, 283–289. doi: 10.1016/j.det.2017.02.002 Simpson, E. L., Bieber, T., Guttman-Yassky, E., Beck, L. A., Blauvelt, A., Cork, M. J., et al. (2016). Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N. Engl. J. Med. 375, 2335–2348. doi: 10.1056/nejmoa1610020 Simpson, E. L., Lacour, J. P., Spelman, L., Galimberti, R., Eichenfield, L. F., Bissonnette, R., et al. (2020a). Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br. J. Dermatol. 183, 242–255. doi: 10.1111/bjd.18898 Simpson, E. L., Sinclair, R., Forman, S., Wollenberg, A., Aschoff, R., Cork, M., et al. (2020b). Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, doubleblind, randomised, placebo-controlled, phase 3 trial. Lancet 396, 255–266. doi: 10.1016/S0140-6736(20)30732-7 Soares, J., Lopes, C., Tavaria, F., Delgado, L., and Pintado, M. (2013). A diversity profile from the staphylococcal community on atopic dermatitis skin: a molecular approach. J. Appl. Microbiol. 115, 1411–1419. doi: 10.1111/jam. 12296 Spaulding, A. R., Salgado-Pabón, W., Kohler, P. L., Horswill, A. R., Leung, D. Y. M., and Schlievert, P. M. (2013). Staphylococcal and streptococcal superantigen exotoxins. Clin. Microbiol. Rev. 26, 422–447. doi: 10.1128/CMR.001 04-12 Spaulding, A. R., Satterwhite, E. A., Lin, Y. C., Chuang-Smith, O. N., Frank, K. L., Merriman, J. A., et al. (2012). Comparison of Staphylococcus aureus strains for ability to cause infective endocarditis and lethal sepsis in rabbits. Front. Cell. Infect. Microbiol. 2:18. doi: 10.3389/fcimb.2012.00018 Suh, L., Coffin, S., Leckerman, K. H., Gelfand, J. M., Honig, P. J., and Yan, A. C. (2008). Methicillin-Resistant Staphylococcus aureus colonization in children with atopic dermaitis. Pediatr. Dermatol. 25, 528–534. doi: 10.1111/j.1525-1470. 2008.00768.x Frontiers in Microbiology | www.frontiersin.org 18 January 2021 | Volume 11 | Article 567090 fmicb-11-567090 December 31, 2020 Time: 11:20 # 19 Ogonowska et al. Staphylococcus aureus in Atopic Dermatitis Sule, O., Brown, N. M., Willocks, L. J., Day, J., Shankar, S., Palmer, C. R., et al. (2007). Fusidic acid-resistant Staphylococcus aureus (FRSA) carriage in patients with atopic eczema and pattern of prior topical fusidic acid use. Int. J. Antimicrob. Agents 30, 78–82. doi: 10.1016/j.ijantimicag.2007. 02.015 Syed, A. K., Reed, T. J., Clark, K. L., Boles, B. R., and Kahlenberg, J. M. (2015). Staphlyococcus aureus phenol-soluble modulins stimulate the release of proinflammatory cytokines from keratinocytes and are required for induction of skin inflammation. Infect. Immun. 83, 3428–3437. doi: 10.1128/IAI.00401-15 Taskapan, M. O., and Kumar, P. (2000). Role of staphylococcal superantigens in atopic dermatitis: from colonization to inflammation. Ann. Allergy Asthma Immunol. 84, 3–12. doi: 10.1016/S1081-1206(10)62731-7 Tomi, N. S., Kränke, B., and Aberer, E. (2005). Staphylococcal toxins in patients with psoriasis, atopic dermatitis, and erythroderma, and in healthy control subjects. J. Am. Acad. Dermatol. 53, 67–72. doi: 10.1016/j.jaad.2005.02.034 Totté, J. E. E., van der Feltz, W. T., Hennekam, M., van Belkum, A., van Zuuren, E. J., and Pasmans, S. G. M. A. (2016). Prevalence and odds of Staphylococcus aureus carriage in atopic dermatitis: a systematic review and meta-analysis. Br. J. Dermatol. 175, 687–695. doi: 10.1111/bjd.14566 Tubby, S., Wilson, M., and Nair, S. P. (2009). Inactivation of staphylococcal virulence factors using a light-activated antimicrobial agent. BMC Microbiol. 9:211. doi: 10.1186/1471-2180-9-211 Valour, F., Tasse, J., Trouillet-Assant, S., Rasigade, J. P., Lamy, B., Chanard, E., et al. (2014). Methicillin-susceptible Staphylococcus aureus clonal complex 398: high prevalence and geographical heterogeneity in bone and joint infection and nasal carriage. Clin. Microbiol. Infect. 20, O772–O775. doi: 10.1111/1469-0691. 12567 van Cleef, B. A. G. L., Monnet, D. L., Voss, A., Krziwanek, K., Allerberger, F., Struelens, M., et al. (2011). Livestockassociated methicillinresistant Staphylococcus aureus in humans. Europe Emerg. Infect. Dis. 17, 502–505. doi: 10.3201/eid1703.101036 Wainwright, M., Maisch, T., Nonell, S., Plaetzer, K., Almeida, A., Tegos, G. P., et al. (2017). Photoantimicrobials—are we afraid of the light? Lancet Infect. Dis. 17, e49–e55. doi: 10.1016/S1473-3099(16)30268-7 Weidinger, S., Baurecht, H., and Schmitt, J. (2017). A 5-year randomized trial on the safety and efficacy of pimecrolimus in atopic dermatitis: a critical appraisal. Br. J. Dermatol. 177, 999–1003. doi: 10.1111/bjd.15827 Woo, T. E., and Kuzel, P. (2019). Crisaborole 2% Ointment (Eucrisa) for atopic dermatitis. Skin Ther. Lett. 24, 4–6. Worm, M., Simpson, E. L., Thaçi, D., Bissonnette, R., Lacour, J.-P., Beissert, S., et al. (2020). Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis. JAMA Dermatol. 156:131. doi: 10.1001/jamadermatol.2019.3617 Yagi, S., Wakaki, N., Ikeda, N., Takagi, Y., Uchida, H., Kato, Y., et al. (2004). Presence of staphylococcal exfoliative toxin A in sera of patients with atopic dermatitis. Clin. Exp. Allergy 34, 984–993. doi: 10.1111/j.13652222.2004.1687.x Yarwood, J. M., Leung, D. Y. M., and Schlievert, P. M. (2000). Evidence for the involvement of bacterial superantigens in psoriasis, atopic dermatitis, and Kawasaki syndrome. FEMS Microbiol. Lett. 192, 1–7. doi: 10.1016/S03781097(00)00400-6 Yeung, M., Balma-Mena, A., Shear, N., Simor, A., Pope, E., Walsh, S., et al. (2011). Identification of major clonal complexes and toxin producing strains among Staphylococcus aureus associated with atopic dermatitis. Microbes Infect. 13, 189–197. doi: 10.1016/j.micinf.2010.10.023 Yu, J., Luo, Y., Zhu, Z., Zhou, Y., Sun, L., Gao, J., et al. (2019). A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor. J. Allergy Clin. Immunol. 143, 2108.e12–2119.e12. doi: 10.1016/j.jaci.2018.11.036 Zollner, T. M., Wichelhaus, T. A., Hartung, A., Von Mallinckrodt, C., Wagner, T. O. F., Brade, V., et al. (2000). Colonization with superantigen-producing Staphylococcus aureus is associated with increased severity of atopic dermatitis. Clin. Exp. Allergy 30, 994–1000. doi: 10.1046/j.1365-2222.2000.00848.x Zuuren, E. J., Fedorowicz, Z., and Arents, B. W. M. (2017). Emollients and moisturizers for eczema: abridged cochrane systematic review including GRADE assessments. Br. J. Dermatol. 177, 1256–1271. doi: 10.1111/bjd.15602 Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Copyright © 2021 Ogonowska, Gilaberte, Bara´ nska-Rybak and Nakonieczna. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Microbiology | www.frontiersin.org 19 January 2021 | Volume 11 | Article 567090