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

micb-11-567090 Decembe 31, 2020 Time: 11:20 # 1 REVIEW published: 11 Janua y 2021 doi: 10.3389/ micb.2020.567090 Edi ed by: Fabian Cieplik, Uni e si y Medical Cen e Regensbu g, Ge many Re iewed by: Te uaki Naka suji, Uni e si y o Cali o nia, San Diego, Uni ed S a es Michael O o, Na ional Ins i u es o Heal h (NIH), Uni ed S a es *Co espondence: Joanna Nakonieczna joanna.nakonieczna @bio ech.ug.edu.pl o cid.o g/0000-0002-2420-664X Special y sec ion: This a icle was submi ed o An imic obials, Resis ance and Chemo he apy, a sec ion o he jou nal F on ie s in Mic obiology Recei ed: 29 May 2020 Accep ed: 14 Decembe 2020 Published: 11 Janua y 2021 Ci a ion: Ogonowska P, Gilabe e Y, Ba a ´ nska-Rybak W and Nakonieczna J (2021) Coloniza ion Wi h S aphylococcus au eus in A opic De ma i is Pa ien s: A emp s o Re eal he Unknown. F on . Mic obiol. 11:567090. doi: 10.3389/ micb.2020.567090 Coloniza ion Wi h S aphylococcus au eus in A opic De ma i is Pa ien s: A emp s o Re eal he Unknown Pa ycja Ogonowska1, Yolanda Gilabe e2, Wiole a Ba a ´ nska-Rybak3and Joanna Nakonieczna1* 1Labo a o y o Molecula Diagnos ics, In e collegia e Facul y o Bio echnology Uni e si y o Gda ´ nsk and Medical Uni e si y o Gda ´ nsk, Gda ´ nsk, Poland, 2Depa men o De ma ology, Uni e si y Hospi al Miguel Se e , Za agoza, Spain, 3Depa men o De ma ology, Vene eology and Alle gology, Medical Uni e si y o Gda ´ nsk, Gda ´ nsk, Poland A opic de ma i is (AD) pa ien s a e massi ely colonized wi h S aphylococcus au eus (S. au eus) in lesional and non-lesional skin. A skin in ec ion may become sys emic i le un ea ed. O in e es , he incidence o mul i-d ug esis an S. au eus (MRSA) in AD pa ien s is highe as compa ed o a heal hy popula ion, which makes ea men e en mo e challenging. In o ma ion on he speci ic gene ic backg ound o S. au eus accompanying and/o causing AD la es would be o g ea impo ance in e ms o possible ea men op ion de elopmen . In his e iew, we summa ized he da a on he p e alence o S. au eus in gene al in AD skin, and he p e alence o speci ic clones ha migh be associa ed wi h la es o eczema. We pu ou special in e es in he p esence and ole o s aphylococcal en e o oxins as impo an i ulence ac o s in he epidemiology o AD-de i ed S. au eus. Also, we summa ize he p esen and po en ially use ul u u e an i-s aphylococcal ea men . Keywo ds: epidemiology o S. au eus, MRSA, s aphylococcal en e o oxins, an is aphylococcal pho odynamic ea men , i ulence ac o INTRODUCTION A opic de ma i is (AD), also known as a opic eczema, is a ch onic and elapsing in lamma o y skin diso de . I may coexis wi h o he a opic condi ions: alle gic hini is (hay e e ), b onchial as hma and ood alle gy. AD mainly a ec s in an s and young child en. Ne e heless, i can pe sis o appea du ing pube y and adul hood. AD occu s commonly in 15–30% o child en and 2–10% o adul s wo ldwide (Sil e be g, 2017). In 1980, Hani in and Rajka p oposed c i e ia o diagnosing AD. Acco ding o he published guidelines, pa ien s diagnosed wi h AD should p esen h ee o mo e basic ea u es (e.g., p u i us, licheni ica ion, a opic his o y) and h ee o mo e mino ea u es (e.g., xe osis, ea ly age o onse , ood in ole ance) (Hani in and Rajka, 1980). Fu he mo e, a ious sco ing sys ems ha e been es ablished o measu e disease se e i y. SCORAD (Se e i y Sco ing Index o A opic De ma i is) e alua es he in ensi y o a opic signs in gene al in addi ion o he symp oms (p u i us and sleep) (Kunz e al., 1997), whe eas EASI (Eczema A ea and Se e i y Index) e alua es he se e i y o AD in ou di e en pa s o he body (head and neck, uppe limbs, unk and lowe limbs) (Hani in e al., 2001;Housman e al., 2002). SASSAD (Six A ea Six Sign A opic De ma i is A opic Sco e) less used includes six signs o AD (c acking, d yness, e y hema, exco ia ion, exuda ion, and licheni ica ion), hei se e i y in a ou -poin scale (0—absen , 1—mild, 2—mode a e and 3—se e e) on he mos F on ie s in Mic obiology | www. on ie sin.o g 1Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 2 Ogonowska e al. S aphylococcus au eus in A opic De ma i is FIGURE 1 | Va ious sco ing sys ems o diagnosing a opic de ma i is. ollowing si es o di e en pa s o he body (head and neck, a ms, hands, unk, legs, and ee ) (Figu e 1;Be h-Jones and Be h- Jones, 1996). Cu en ly, AD is conside ed a mul i ac o ial skin diso de , wi h s ill no ully unde s ood pa hogenesis. The de elopmen o AD is a esul o in e ac ions be ween skin ba ie de ec s and gene ic, immunological and en i onmen al ac o s (e.g., dus mi e, obacco smoke, soap, die , ai pollu ion, hygiene, s ess) (Ring e al., 1992;Bonamon e e al., 2019). Pa ien s su e ing om a opic eczema e ealed signi ican ly educed quali y o li e due o i ching, which leads o sleep dis u bances (Blome e al., 2016). The se e e o m o AD had a signi ican impac on he quali y o li e in adul pa ien s compa ed o he mild and mode a e ypes o AD (Chiesa Fuxench e al., 2019). Mo eo e , AD is a se ious socio-economic p oblem in heal h ca e uni s because o he long ea men du a ion and inancial cos s (Ca oll e al., 2005). In addi ion o he long- e m and bu densome ea men o AD pa ien s, coloniza ion by S aphylococcus au eus is ano he se ious p oblem. S aphylococcus au eus is associa ed wi h he se e i y, pa hogenesis and exace ba ion o AD. INCREASED STAPHYLOCOCCUS AUREUS COLONIZATION RATE FOR AD PATIENTS The phenomenon o S. au eus coloniza ion in AD pa ien s has been known o a long ime (Leyden and Ma ples, 1973;Hause e al., 1985). Hause e al. demons a ed highe S. au eus densi y, S. au eus ac ion (SAF index) and o al CFU/cm2(CFU–colony o ming uni s) in he lesional skin in AD pa ien s han in he heal hy con ol g oup (Hause e al., 1985). In child en su e ing om AD, S. au eus coloniza ion a e is highe han in he heal hy g oup and a ec s 57–100% o child en (Bunikowski e al., 2000; A kw igh e al., 2001;Lo e al., 2010;Pascolini e al., 2011). Mo e han 40% o AD child en a e colonized bo h on he lesional skin and in he an e io na es (Pascolini e al., 2011). In child en wi h AD, he ca iage o he S. au eus s ains in he an e io na es could be a po en ial sou ce o ecoloniza ion (Pa el e al., 2001). Resul s conce ning S. au eus p esence om AD child en a e summa ized in Table 1. Rega ding S. au eus coloniza ion in adul pa ien s, 54–100% (B eue e al., 2002;Tomi e al., 2005;Gong e al., 2006;Kim e al., 2009;Na e al., 2012;Rojo e al., 2014;Clausen e al., 2017, 2019) su e ing om AD we e colonized by his species. S. au eus isola es o med a ese oi in he nose in AD pa ien s. I can be di used by au o ansmission on he skin a ea (B eue e al., 2002). The mos colonized si e is lesional skin (56–96.2%) (Ma sui e al., 2000;Pa k e al., 2016;To é e al., 2016;Als e holm e al., 2017), nose (46.1–64.1%) (Na e al., 2012;Pa k e al., 2016;To é e al., 2016;Clausen e al., 2017), and non-lesional skin (28–39%) (Ma sui e al., 2000;To é e al., 2016;Clausen e al., 2017). Se e al s udies demons a ed ha 65–77.3% (B eue e al., 2002;Tomi e al., 2005;Na e al., 2012) o AD pa ien s we e colonized bo h in he an e io na es and on he skin, whe eas only 10.2% o heal hy con ol subjec s we e colonized on he skin (Ma sui e al., 2000). Als e holm e al. (2017) ound ha 55% o he AD pa ien s we e pe sis en ca ie s o S. au eus. Mo eo e , pe sis en S. au eus ca ie s had a highe SCORAD han in e mi en ca ie s o non- ca ie s. I u ns ou ha no only he nose bu also he skin could be an impo an ese oi o S. au eus in AD pa ien s (Als e holm e al., 2017). F equen ecoloniza ion by S. au eus be ween nose and skin was obse ed, which can con ibu e o he se e i y o AD (Chiu e al., 2009). Resul s conce ning he dis ibu ion o S. au eus in adul s a e summa ized in Table 2. High S. au eus coloniza ion a e is obse ed in bo h g oups, child en and adul s. Coloniza ion a e inc eases wi h he se e i y o he AD, and i ac s as an agg a a ing ac o exace ba ing in lamma ion (B eue e al., 2002). Also, coloniza ion wi h S. au eus in AD pa ien s could be a po en isk o a ious in asi e in ec ions, e.g., bac e emia, sep ic shock, os eomyeli is, nec o izing pneumonia, o sep ic a h i is (Pa el and Jahnke, 2015). MRSA VS. MSSA DISTRIBUTION IN ATOPIC DERMATITIS Among S. au eus isola es, me hicillin- esis an S. au eus (MRSA) cons i u es an impo an and signi ican g oup ha equi es pa icula conce n. MRSA is a g oup o s ains ha a e esis an o mul iple β-lac am an ibio ics (cephalospo ins, ca bapenems, monobac ams, and penicillins). This pheno ype esul s in limi ed ea men op ions, including o skin in ec ions (Rangel and Palle , 2018). I has been demons a ed ha among S. au eus s ains colonizing AD pa ien s, he pe cen age o MRSA is 4–13 imes highe han in a heal hy popula ion (Suh e al., 2008;Lo e al., 2010). Cu en ly, h ee p o iles o MRSA a e dis inguished: hospi al-associa ed (HA-MRSA), communi y-associa ed (CA- MRSA), and li es ock-associa ed MRSA (LA-MRSA). Ini ially, epidemiological in es iga ions indica ed ha MRSA in ec ions ela ed only o hospi alized pa ien s (HA-MRSA). Howe e , la e i u ned ou ha MRSA can also be isola ed om in ec ed F on ie s in Mic obiology | www. on ie sin.o g 2Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 3 Ogonowska e al. S aphylococcus au eus in A opic De ma i is TABLE 1 | The dis ibu ion o S. au eus coloniza ion and oxins p oduc ion in child en wi h a opic de ma i is. Re e ences Examined g oups Si es o isola ion Coloniza ion s aphylococcus au eus Toxins p oduc ion Bunikowski e al. (2000) Ge many Child en wi h AD (n= 74) Heal hy con ol pa ien s (n= 25) Una ec ed and eczema ous skin lesions Neck W is Elbow E osi e eczema ous lesions AD pa ien s 60 (81%) we e S. au eus posi i e [including 40 (53%) oxigenic S. au eus s ains] Heal hy con ols 5 (20%) we e S. au eus posi i e [including 1 oxigenic S. au eus s ain] AD pa ien s sea: 12, seb: 9, sec: 12, sed:3, ss -1: 9 Heal hy con ols sea: 1 A kw igh e al. (2001) Uni ed Kingdom Child en wi h AD (n= 28) Eczema ous lesions Na es Each o he examined pa ien s was colonized Skin sea: 3 (11%), seb: 1 (4%), sec: 7 (25%), sed: 1 (4%), see: 0, seg&sei: 6 (21%), seh: 0, ss -1: 3 (11%) Nose sea: 2 (7%), seb: 0, sec: 3 (11%), sed: 1 (4%), see: 0, seg&sei: 5 (17%), seh: 1 (4%), ss -1: 2 (7%) Lomhol e al. (2005) Denma k Child en wi h AD (n= 11) An e io na es Axillae A ea o ac i e eczema Pe ineum No da a sea: 8 (29%), seb: 1 (4%), sec: 1 (4%), sed: 0 (0%), ss -1: 0 (0%) Lo e al. (2010) Taiwan Child en wi h AD (n= 133) Child en wi h AD and SSTI (n= 20) Heal hy con ols (n= 490) The an e io na es Child en wi h AD 67 isola es we e posi i e o S. au eus (23 MRSA and 44 MSSA) Child en wi h AD and SSTI 20 isola es we e posi i e o S. au eus (12 MRSA and 8 MSSA) Heal hy con ols 170 isola es we e posi i e o S. au eus (44 MRSA and 126 MSSA) Resul s om molecula cha ac e is ics o 79 MRSA isola es om 643 child en Child en wi h AD sea: 1 (4%), seb: 20 (87%), sec: 2 (9%), sed:0,seg/sei: 1 (4%), seh: 1 (4%), ss -1: 2 (9%), Child en wi h AD and SSTI sea: 0, seb: 12 (100%), sec: 0, sed: 0, seg/sei:0,seh: 1 (8%), ss -1: 0, Heal hy con ols sea: 3 (7%), seb: 28 (64%), sec: 11 (25%), sed: 1 (2%), seg/sei: 11 (25%), seh:0, ss -1: 7 (16%) Pascolini e al. (2011) I aly Child en wi h AD (n = 117) Heal hy con ols (n= 90) Skin lesions No mal skin a eas Na es Child en wi h AD 66 pa ien s (57%) - lesional skin and na es: 47 (40.2%) - na es: 19 (16.2%) - unin ol ed skin: 4 (3.4%) Heal hy child en 18 pa ien s (20%) - na es: 18 - unin ol ed skin: 0 En e o oxins 71 posi i e among 90 S. au eus s ains Tss -1 40 posi i e among 90 S. au eus s ains Pa k e al. (2013) Ko ea In an s wi h AD (n = 188) Child en wi h AD (n= 267) Con ol g oup— pa ien s wi h u ica ia (n= 247) Skin lesions (acu e and ch onic) In an s- acu e lesion: 50% (18/36) - ch onic lesion: 18.5% (28/151) Child en- acu e lesion: 80% (44/55) - ch onic lesion: 41.8% (90/215) No da a Gilabe e e al. (2015) Spain Child en wi h AD (n= 114) Clinically unin ec ed lesional skin (an ecubi al o popli eal a eas) Na es Skin: 32/113 (28.3%) Na es: 20/85 (23.5%) All S. au eus s ains we e MSSA excep one MRSA isola ed om he skin Skin and nasal isola es seb: 1 (2.5%), sec: 2 (5%), ss -1: 22 (55%) Skin isola es seb: 0, sec: 2 (7.7%), ss -1: 13 (50%) Abad e al. (2019) B azil Child en wi h AD (n= 117)—2 mon hs–14 yea s old Nasal swabs 97/117 o pa ien s (82.90%) we e colonized wi h S. au eus - 26/97 (22.22%) MRSA - 71/97 (60.68%) MSSA No da a F on ie s in Mic obiology | www. on ie sin.o g 3Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 4 Ogonowska e al. S aphylococcus au eus in A opic De ma i is TABLE 2 | The dis ibu ion o S. au eus coloniza ion and oxins p oduc ion in adul s wi h a opic de ma i is. Re e ences Examined g oups Si es o isola ion Coloniza ion o s aphylococcus au eus Toxins p oduc ion Zollne e al. (2000) Ge many AD pa ien s (n= 33) A opic con ols (n= 21) Heal hy con ols (n= 50) AD pa ien s: mucous memb anes (nose and h oa ), in ol ed skin Heal hy con ols: heal hy skin o he elbows AD pa ien s: 23/33 (69.70%) A opic con ols: 9/21 (42.86%) Heal hy con ols: 15/50 (30%) AD pa ien s 13/23 (57%) isola es p oduced SEs seb (5/13, 38%), sec (1/13, 8%), sed (1/13, 8%), ss -1 (3/13, 23%) A opic con ols 3/9 (33%) isola es p oduced SEs sea (2/3, 66%), seb (1/3, 33%), ss -1 (1/3, 33%) Heal hy con ols 5/15 (33%) isola es p oduced SEs sea (1/5, 20%), seb (1/5, 20%), ss -1 (3/5, 60%) B eue e al. (2002) Ge many Pa ien s wi h AD–adul s (n= 66) Skin An e io na es 62 o he 66 pa ien s (94%) - skin(+), nose(+): 51 (77.3%) - skin(+), nose(−): 7 (10.6%) - skin(−). nose(+): 4 (6.1%) - skin(−), nose(−): 4 (6.1%) Cu aneous and nasal isola es om 32 pa ien s we e included in he s udy. 10 (31%) o he pa ien s we e colonized wi h oxigenic S. au eus Skin sea = sed >seb >sec = ss -1 Nose sed >seb >sea =sec ss -1 was no de ec ed Schlie e e al. (2008) Uni ed S a es G oup 1 isola es Pa ien s wi h s e oid- esis an a opic de ma i is (n= 78) G oup 2 isola es Heal hy women aginas (n= 30) G oup 3 isola es Pa ien s wi h a opic de ma i is (n= 22) G oup 1 isola es: 4 he mos a ec ed eczema ous lesions No da a G oup 1 sea: 37 (47%), seb: 33 (42%), sec: 23 (29%), sed: 38 (49%), see: 33 (42%), sei: 38 (49%), ss -1: 27 (35%) G oup 2 sea: 8 (27%), seb: 3 (10%), sec: 9 (30%), sed: 4 (13%), see: 6 (20%), sei: 10 (33%), ss -1: 12 (40%) G oup 3 sea: 4 (18%), seb: 2 (9%), sec: 2 (9%), sed: 1 (4.5%), see: 6 (27%), sei: 10 (45%), ss -1: 11 (50%) Kim e al. (2009) Ko ea Adolescen o adul pa ien s wi h AD (n= 42) The eczema ous lesions: La e al neck Fo ea m Abdomen Popli eal a ea 35 o he 42 pa ien s (83.3%) sea: 35 (97.2%), seb: 1 (2.8%), sec:0,sed: 5 (13.9%), see: 0, ss -1: 35 (97.2%) Pa k e al. (2013) Ko ea Adul s wi h AD (n= 232) Con ol g oup—pa ien s wi h u ica ia (n= 247) Skin lesions (acu e and ch onic) Adul s - acu e lesions: 87.5% (35/40) - ch onic lesions: 48.9% (93/190) No da a Als e holm e al. (2017) Sweden Pa ien s wi h AD (n= 21) Lesional skin An e io na es Pe ineum Tonsils Non-lesional skin Lesional skin: 57–65% Non-lesional skin: 53–71% An e io na es: 53–67% Tonsils: 24–30% Pe ineum: 32–55% No da a Clausen e al. (2019) Denma k AD pa ien s (n= 63) Lesional skin Non-lesional skin Nose 34 o pa ien s (54%): - lesional skin: 33% - non-lesional skin: 10% - nose: 41% No da a F on ie s in Mic obiology | www. on ie sin.o g 4Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 5 Ogonowska e al. S aphylococcus au eus in A opic De ma i is people ha ha e no been exposed o heal hca e- ela ed isks (CA-MRSA). The i s ou b eak o CA-MRSA was desc ibed in 1981 in he Uni ed S a es (Sa a ola z e al., 1982) and nowadays is associa ed wi h skin and so issue in ec ions (King e al., 2006;Chung e al., 2008). The skin o pa ien s wi h AD could be a a o able ese oi o CA-MRSA. In he Uni ed S a es, 18.3% o AD pa ien s a e colonized wi h CA-MRSA (Chung e al., 2008). Coloniza ion wi h MRSA cons i u es he bes -known isk ac o o de eloping in ec ion and MRSA can be easily ans e ed ia di ec skin- o-skin con ac in he public se ings, e.g., gyms, hus sp eading he bac e ia u he . Repo ed in ecen yea s, LA-MRSA is o animal o igin, bu i has also been de ec ed in humans ( an Clee e al., 2011). I ypically causes skin and so issue in ec ions (SSTI) as well as mo e se e e in ec ions, simila o HA- and CA-MRSA. Some epidemiological da a on he p e alence o LA-MRSA skin and so issue in ec ions accoun o 15% o all MRSA SSTI in ec ions in he communi y (Bu aye e al., 2016). Howe e , simila da a in he AD popula ion a e no cu en ly a ailable. Nasal ca iage o S. au eus plays a i al ole in he epidemiology and pa hogenesis o AD disease. Ne e heless, he dis ibu ion o MRSA s ains among AD pa ien s is s ill di e gen in he wo ldwide popula ion. Among S. au eus-posi i e swabs om he an e io na es o AD pa ien s, 34% we e MRSA, in con as o 26% om heal hy child en (Lo e al., 2010). In ano he s udy ca ied ou in B azilian AD child en, 22.22% o S. au eus isola ed s ains we e MRSA. On he o he hand, when Ko ean AD child en skin lesions we e sc eened, 18.4% S. au eus s ains we e MRSA. Finally, among he isola es om AD child en om I aly, only 7.9% we e MRSA (12.8% om he skin lesion and 4.5% om he nose) (Chung e al., 2008; Pascolini e al., 2011). Mo eo e , hey indica ed ha child en wi h AD who had con ac wi h wounds and pus a home o wi h pe sons colonized by MRSA had an inc eased isk o acquisi ion MRSA. In he case o adul s wi h AD, he o e all dis ibu ion o MRSA isola es seems o be much lowe (Kim e al., 2009) o e en absen (Rojo e al., 2014), as compa ed o he child en in AD popula ion. S udies men ioned abo e indica e ha he dis ibu ion o MRSA isola es among AD pa ien s e lec s an inc eased p e alence o MRSA in he AD popula ion as compa ed o heal hy ones, in pa icula in child en. No ably, among pa ien s exp essing a se e e ype o AD, a highe isk o MRSA acquisi ion wi h ime was epo ed in compa ison o pa ien s wi h a mild o mode a e AD ype (Abad e al., 2019). FACTORS PREDISPOSING TO THE S. AUREUS COLONIZATION One o he main ac o s p edisposing o he S. au eus coloniza ion a e changes in he composi ion o lipids and a y acids in he skin. In he epide mis (especially in he s a um co neum) signi ican ly lowe le el o ce amides and highe amoun o choles e ol was obse ed (Figu e 2;Mu a a e al., 1996;Di Na do e al., 1998). The educ ion o skin lipids le el could explain he ole o hese componen s in main aining he hyd a ion o he skin (Code ch e al., 2003). Simila ly, ce amides and sphingosine le els a e educed in he s a um co neum o AD pa ien s, which may a o S. au eus coloniza ion. I was shown ha sphingosine e eals he an imic obial e ec agains S. au eus (A ikawa e al., 2002). Fu he mo e, S. au eus ha colonized pa ien s wi h AD p oduced an enzyme—ce amidase (Ohnishi e al., 1999). Since ce amides play a c ucial ole in he wa e - e aining in he s a um co neum, ce amidases ac ion lead o he de iciency o ce amides molecules, which is associa ed wi h inc easing ans-epide mal wa e loss and cha ac e is ic d y, c acked skin in pa ien s wi h AD (A ikawa e al., 2002). The le el o an imic obial pep ides (AMPs) and hos de ense pep ides (HDPs), p oduced by ke a inocy es such as de micidin, human β-de ensins and ca helicidin–LL-37 a e ma kedly educed in AD skin, which also conduces o S. au eus coloniza ion and in ec ion (Ong e al., 2002;Roll e al., 2004). These pep ides e icien ly inhibi S. au eus g ow h (Niyonsaba e al., 2017). Th2 cy okines IL-4, IL-13, and IL-31, which a e o e exp essed in AD pa ien s, inhibi ed he exp ession o he human β-de ensins genes (hBD-2 and hBD-3). I is p obably one o he ac o s ha con ibu e o he p oli e a ion o S. au eus, dis u bance o mic obio a composi ion and implica ion in he AD pa hogenesis (Kanda and Wa anabe, 2012). Filagg in (FLG) is an epide mal p o ein which is a pa o he s a um co neum, he main ba ie o he skin. Filagg in is esponsible o hyd a ion, main aining epide mal homeos asis, c ea ing chemical, and s uc u al ba ie unc ion (O’Regan and I ine, 2008). The p ima y unc ion is bonding ke a in cy oskele on in he p ocess o ke a inocy es ma u a ion in he skin laye (Candi e al., 2005;B own and McLean, 2012). Filagg in can ac as a sca old o he connec ion o he lipids laye s (O’Regan e al., 2008). As a esul o ilagg in b eakdown, py olidone ca boxylic acid (PCA) and u ocanic acid (UCA) a e o med, which a e he composi ion o na u al mois u izing ac o (NMF) (Rawlings e al., 1994;O’Regan e al., 2008). This ac o plays a c ucial ole in main aining hyd a ion o he s a um co neum and he app op ia e pH o he skin (Rawlings e al., 1994;O’Regan e al., 2008). Nowadays, mos s udies p o ed ha ilagg in loss-o - unc ion mu a ions play an impo an ole in he agg a a ion p ocess in pa ien s wi h AD (B own and McLean, 2012). Reduced le els o ilagg in cause skin in lamma ion, esul ing om he inc easing pene a ion o alle gens o i i an s (G ube e al., 2011). Fu he mo e, he le els o ilagg in and NMF a e signi ican ly dec eased in AD pa ien s (B own and McLean, 2012). Also, PCA and UCA, ilagg in b eakdown p oduc s ha e been in i o shown o impac S. au eus cell densi y and g ow h a e (Miajlo ic e al., 2010). No ably, in pa ien s wi h a mu a ion in he ilagg in gene (FLG) inc eased S. au eus coloniza ion was showed as compa ed o wild- ype pa ien s (Clausen e al., 2017). In he skin, pH le el plays a key ole in main aining he p ope ba ie unc ion in he epide mis, p o ec ion agains pa hogens and con ol o he p ocess o desquama ion. The pH le el o heal hy skin is sligh ly acidic (4.0–6.0). Fa y acids–p oduc s o he phospholipid hyd olysis in sebum and swea , main ain he low pH le el (Chan and Mau o, 2011). The e is an associa ion F on ie s in Mic obiology | www. on ie sin.o g 5Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 6 Ogonowska e al. S aphylococcus au eus in A opic De ma i is FIGURE 2 | Fac o s p edisposing o he S. au eus coloniza ion. be ween he lowe pH le el and he educed exp ession o p o eins, in pa icula , hose in ol ed in adhe ence o he skin by S. au eus (e.g., p o ein A, clumping ac o B, ib onec in-binding p o ein A) (Leung, 2013). The e o e, changes in he pH le el owa d mo e alkaline a e one o he ac o s, acili a ing S. au eus coloniza ion and g ow h in AD pa ien s (O’Regan and I ine, 2008;P oksch e al., 2008;Clausen e al., 2019). The pH 7.0– 8.0 has been shown op imal o S. au eus adhesion o human ke a inocy es (Mempel e al., 1998). NO MAJOR S. AUREUS CLONES COULD BE ASSIGNED TO ISOLATES FROM AD PATIENTS Due o he equen occu ence o S. au eus in pa ien s wi h AD, as well as he g owing numbe o scien i ic epo s on he mechanisms o immune esponse induc ion by speci ic i ulence ac o s, a na u al ques ion a ises whe he he e a e selec ed S. au eus clones/ ypes associa ed wi h he disease. A “gold s anda d” o de e mine he clonali y o S. au eus s ains, especially MRSA, is PFGE (Pulsed Field Gel Elec opho esis) (He e al., 2014). A speci ic “DNA inge p in ” o an indi idual clone is assigned o a speci ic pulso ype (e.g., A, B, C) (Golding e al., 2015). PFGE geno yping o S. au eus indica ed ha among he isola es om AD child en, he mos common pulso ype was B (48%). In con as , pulso ype A was he mos equen in he heal hy con ol g oup (64%) (Lo e al., 2010). Howe e , Lomhol e al. (2005) indica ed ha 28 a ious S. au eus PFGE pulso ypes could be epo ed o AD pa ien s. Wi h he applica ion o MLST (mul i-locus sequence yping), ha is ano he use ul me hod o mic obial geno yping, Kim e al. (2009) e ealed ha sequence ypes ST188, ST1, ST5, and ST513 we e he mos equen ly iden i ied in he s udied adolescen o adul pa ien s wi h AD (19.4, 13.9, 11.1, and 11.1%, espec i ely). These da a demons a ed he absence o p e ailed geno ype. Addi ionally, mos o he de ec ed lineages (especially ST188 and ST1) we e communi y-acqui ed s ains in con as o only a single ST5, which in Ko ea is associa ed wi h hospi al- acqui ed s ains. Clausen e al. ocused on he dis ibu ion o clonal complexes (CCs) de e mined based on spa yping among s ains isola ed om AD pa ien s. As much as 92% o S. au eus isola es demons a ed iden ical spa ypes in h ee s udied si es (nose, lesional, non-lesional skin). The mos equen spa ypes we e 008, 084, 127, and 948 (Clausen e al., 2017). Di e en esul s we e ob ained by Kim e al. (2009), who iden i ied 189 (19.4%) as he mos equen ype, ollowed by 127 (13.9%), 164 (11.1%), and 304 (8.1%). These esul s con i m he obse a ion on he he e ogenei y o S. au eus s ains isola ed om AD pa ien s. Applying ye ano he yping me hod, namely, CC yping, Yeung e al. (2011) p o ed ha in AD pa ien s (adul s and child en), he mos common clonal complex was CC45 (34 o S. au eus isola es ou o 160), CC5 (23 isola es), CC15 (22 isola es), CC1 (21 isola es), CC30 (11 isola es), and CC398 (8 isola es). In ano he s udy by Rojo e al. (2014) wo g oups o pa ien s we e included as ollows: AD pa ien s (n= 32) and pa ien s who su e ed om o he a opic diseases (as hma, alle gic hini is o ood alle gy, n= 31). Among AD pa ien s, he mos equen CC was CC5 (31.2%), CC15 (18.7%), CC30 (18.7%), and CC45 (15.6%), whe eas CC30 mos ly p e ailed in he con ol g oup (48.3%) (Rojo e al., 2014). Also, i was demons a ed ha 95% o examined samples om AD pa ien s belonged o he same clonal complex in h ee sampling si es (nose, lesional and non-lesional skin). In e es ingly, he au ho s obse ed ha CC1 was iden i ied mo e equen ly in pa ien s wi h ilagg in mu a ions (Clausen e al., 2017). Simila ly, Ha kins e al. ound in he in lamed skin o child en wi h AD ha he mos p e alen clonal complex was CC1 (20%), whe eas CC30 (33%), and CC45 (22%) we e p edominan ly de ec ed in he an e io na es o heal hy child en (Ha kins e al., 2018). Tempo al a ia ion o CC ypes in S. au eus was obse ed in pa ien s wi h mild o mode a e AD whe e 52% o pa ien s F on ie s in Mic obiology | www. on ie sin.o g 6Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 7 Ogonowska e al. S aphylococcus au eus in A opic De ma i is examined du ing ollow up s udy we e colonized by he same CC ype. In e es ingly, nea ly hal o he s udied pa ien s (48%) demons a ed di e en CC ypes du ing he ollow-up s udy, which co ela ed wi h inc eased SCORAD (Clausen e al., 2019). Gene ic a ia ions p esen in S. au eus has been shown o in luence clinical ou come in some essen ial diseases (Messina e al., 2016). The connec ion be ween clonal complex and in ec ions was documen ed o CC8 associa ed wi h sepsis, CC30 associa ed wi h endoca di is o CC398 associa ed wi h nasal ca iage and bone and join in ec ion (Nienabe e al., 2011;Spaulding e al., 2012;Valou e al., 2014). The dis ibu ion o s aphylococcal clonal complexes in AD pa ien s ha has been analyzed h oughou he ecen yea s poin s o g ea he e ogenei y, and no speci ic clone/clones p e ailed in his g oup o pa ien s. Mo eo e , obse a ions p o ed ha popula ions o S. au eus isola ed om AD pa ien s a e e y clonal, and ha cha ac e is ic i ulence ac o a ian s ha ha e been shown o con ibu e o AD may occu in di e en clonal lineages. This u he means ha his is a he unlikely o cha ac e ize speci ic S. au eus lineages associa ed wi h AD and disease se e i y, a leas based on adi ional yping me hods (Kim e al., 2009;Yeung e al., 2011;Rojo e al., 2014;Clausen e al., 2017). The only example o a co ela ion be ween S. au eus gene ic backg ound and AD was he one ound by Clausen e al., whe e CC1 clone was he mos commonly de ec ed among AD pa ien s (22% o all colonized pa ien s) and signi ican ly mo e p e alen in ilagg in mu a ion ca ie s (Clausen e al., 2018). Ne e heless, conside ing he abo e obse a ion and he dynamic e olu ion o he S. au eus species based on he su i al o only hose popula ions ha can su i e in gi en condi ions (e.g., in a de ec i e a opic skin), he exis ence o AD-speci ic geno ype(s) canno be excluded. S. au eus gene ic a ia ions ha migh con ibu e o a pa icula clinical ou come (like in ec ion o a opic skin) migh be p esen a di e en le els: clonal, gene, o a he le el o gene polymo phisms. The e o e, de ailed knowledge abou he bac e ial gene ic a ia ion is needed o unde s and be e he ole o S. au eus in he pa hogenesis o AD. A NEW CONCEPT OF STRAIN-SPECIFIC COLONIZATION OF S. AUREUS IN AD T adi ional geno yping me hods allow he di e en ia ion o s aphylococcal isola es om AD pa ien s. These me hods, howe e , ha e hei esolu ion limi a ions, which did no allow iden i ica ion o speci ic gene ic ea u es o AD-de i ed S. au eus. A he same ime, he e a e unc ional di e ences mani es ed by al e ed immune esponses in he skin be ween AD S. au eus s ains s. non-AD S. au eus s ains. I was obse ed ha only AD-de i ed S. au eus s ains al e ed T cell esponse ia Lange hans cells (Iwamo o e al., 2017), and only AD-de i ed s ains accumula ed in lysosomes and induced IL-1αp oduc ion ia Toll-like ecep o 9 (Mo iwaki e al., 2019). The obse ed di e ences ha e been a ibu ed o su ace p o eins (Iwamo o e al., 2017;Mo iwaki e al., 2019). In line wi h hose epo s, S. au eus isola ed om AD bu no om heal hy ca ie s induced s ong in lamma ion in he mouse model o AD (By d e al., 2017). Whole-genome sequencing o AD-de i ed S. au eus e ealed genes coding o p o eins associa ed wi h in ec ion, ca o enoid p oduc ion, o β-lac am esis ance o be associa ed wi h AD coloniza ion (By d e al., 2017). Analyzing AD mic obiome sugges s ha AD pa ien s may be p e e en ially colonized by hose S. au eus s ains ha can syn hesize yp ophan (Fyh quis e al., 2019). I was expe imen ally shown, howe e , ha yp ophan me aboli es on a opic skin a e signi ican ly educed, and he e o e s ains ha do no equi e exogenous yp ophan o g ow h may be p e e ed (Yu e al., 2019). The concep o speci ic S. au eus isola es ha ha e a mo e signi ican po en ial o colonize a opic skin o induce an immune e ec in AD pa ien s has de eloped signi ican ly in ecen yea s. Mainly due o he esul s o s udies linking he p oduc ion o S. au eus δ- oxin wi h alle gic skin diseases (Nakamu a e al., 2013). S aphylococcus au eus once es ablished on he skin, p omo es in lamma ion h ough mul iple pa hways. Recen wo k om se e al labo a o ies has ad anced ou unde s anding o how he skin coloniza ion o S. au eus p omo es in lamma o y skin diseases. The gene al o e iew o he pa hways in ol ed in S. au eus and i s i ulence ac o s con ibu ion o AD is p esen ed in Figu e 3. I has been documen ed ha S. au eus is able no only o colonize he su ace o he skin, bu i also pene a es he de mis, whe e he bac e ium can come in o di ec con ac wi h immune cells and s imula e he p oduc ion o p oin lamma o y cy okines (Naka suji e al., 2016). S. au eus p oduces a ange o po en i ulence ac o s ha appea ed o play a c ucial ole in he in lamma ion p ocess d i en by he bac e ium, e.g., PSMs (phenol soluble modulins), p o eases (au eolysin, V8 p o ease, SspA se ine p o ease, ScpA cys eine p o ease), supe an igens (s aphylococcal en e o oxin A, B, TSST-1). PSMαhas been shown o induce exp ession o cy okines in ke a inocy e cell lines as well as in a mouse model o AD ia lysis o ke a inocy es, which led o he elease o in lamma o y cy okines (Syed e al., 2015). Ano he PSM ep esen a i e, namely δ- oxin was iden i ied in abundan amoun s in cul u e supe na an s o S. au eus isola ed om he skin o AD pa ien s and was shown o be a po en induce o mas cells deg anula ion sugges ing o he i s ime a link be ween S. au eus coloniza ion and alle gic skin diseases (Nakamu a e al., 2013). In his case, he mechanism o ac ion was di e en om o he PSMs, as δ- oxin (PSMγ) did no cause cell lysis bu a he induced signaling pa hway leading o inc eased IgE, IL-4 le els (Figu e 3). PSMs a e c i ical o he induc ion o IL-17 p oducing cells, namely γδTcells o ILC3 ( ype 3 lymphoid cells), which a e media o s o skin in lamma ion in esponse o S. au eus (Nakagawa e al., 2017). Depending on he dep h bac e ia can each in he skin–epide mis s. de mis, di e en hos esponse can be elici ed. Epicu aneous exposu e o S. au eus p omo es in lamma ion ia IL-36, p oduced mos ly by ke a inocy es, whe eas in ade mal challenge p omo es IL-1β induc ion o in lamma ion (Liu e al., 2017). The pene a ion dep h has been shown o c i ically depend on an impo an g oup o i ulence ac o s p oduced by he bac e ium, namely se ine p o eases (Naka suji e al., 2016). F on ie s in Mic obiology | www. on ie sin.o g 7Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 8 Ogonowska e al. S aphylococcus au eus in A opic De ma i is FIGURE 3 | Pa hways in ol ed in S. au eus’ i ulence ac o s con ibu ion o AD. (C ea ed wi h BioRende ). Toll-like ecep o s (TLRs), ecognizing a ious bac e ial an igens (e.g., cell wall componen s), ansduce a signal h ough MyD88 (Myeloid di e en ia ion p ima y esponse gene-88) signaling pa hway ha leads o ac i a ion o NFκB ansc ip ion ac o and p oduc ion o p oin lamma o y cy okines (Kuo e al., 2013). Recen ly, MyD88-dependen signaling was demons a ed a c i ical pa hway ac i a ed in esponse o s aphylococcal i ulence ac o s–PSMα(Liu e al., 2017) and SEB (Faßbende e al., 2017). SEB is one o he bes -s udied en e o oxins in he con ex o in lamma ion in AD pa ien s, nex o SEA and TSST-1. Howe e , in ecen yea s, expe imen al da a on o he membe s o his g oup o i ulence ac o s ha e eme ged, expanding ou unde s anding o he mechanisms linking S. au eus and AD (Aziz e al., 2019; O ali e al., 2019). A ansc ip omic app oach o s udy ke a inocy e esponse o SEB o TSST-1 has been shown o up- o down egula e mo e han 3,000 genes, con i ming a p e iously p oposed signaling pa hway h ough CD40 ecep o (Schlie e e al., 2020). These phenomena equi e e en mo e de ailed knowledge, bu i u ns ou ha S. au eus may play a i al ole in he de elopmen o AD in a s ain-speci ic manne . The expe imen al da a ying o p o ide an answe o a ques ion whe he S. au eus causes AD o i s inc eased su i al on AD skin is a consequence o he disease is only s a ing o eme ge. Mo e and mo e puzzles add up o a comple e pic u e ha may soon allow us o unde s and be e he molecula mechanism o a complex ela ion be ween S. au eus and AD (Geoghegan e al., 2018). AN AMBIGUITY OF STAPHYLOCOCCAL ENTEROTOXINS (SEs) IN ATOPIC DERMATITIS F om he as epe oi e o S. au eus’ i ulence ac o s, we will ocus on a speci ic g oup–en e o oxins, which S. au eus p oduces dozens o a ie ies. The py ogenic oxin supe an igen (PTSA) amily is he g oup o s aphylococcal oxins ha includes he ollowing clus e s: s aphylococcal en e o oxins (SEs), s aphylococcal en e o oxin- like oxins (SEls), and oxic shock synd ome oxin (TSST-1). The nomencla u e dis inguished SEs (SEA, SEB, SEC, SED, SEE) om SEls (SElG, SElH, SElJ, SElK, SElL, SElM, SElN, SElO, SElP, and SElQ) is based on hei causing (SEs) o no causing (SEls) emesis in humans (Figu e 4;Lina e al., 2004). S aphylococcal en e o oxins (SEs) a e known as bac e ial i ulence ac o s ha con ibu e o he de elopmen o many human diseases, including oxic shock synd ome o ood poisoning (Ha is e al., 1993;Balaban and Rasooly, 2000;O ega e al., 2010;Pinchuk e al., 2010). Many au ho s ha e indica ed a ole o SEs in he cou se o AD by ac ing as ac o s agg a a ing and exace ba ing he in lamma ion o AD skin (Bunikowski e al., 2000;Taskapan and Kuma , 2000;Ya wood e al., 2000;Zollne e al., 2000). Mo eo e , he e a e indica ions o he causa i e ole o SEs in he cou se o AD. The mos common ea u e o SEs is ha hey possess supe an igenic p ope ies (Spaulding e al., 2013). Supe an igens (SAgs) can bind as in ac p o eins o he T-cell an igen ecep o (TCR) and he majo his ocompa ibili y complex II F on ie s in Mic obiology | www. on ie sin.o g 8Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 9 Ogonowska e al. S aphylococcus au eus in A opic De ma i is FIGURE 4 | Th ee clus e s o s aphylococcal oxins. (MHC II) ou side hei binding si e (Fink e al., 1986) hus, s imula ing massi e p oli e a ion o nonspeci ic T cells and elease o p oin lamma o y cy okines (Ha is e al., 1993; Hol e e e al., 2006). Because o in e es in SEs as an agg a a ing ac o in AD, hei dis ibu ion in AD-de i ed S. au eus isola es was a ma e o deep in e es . The main ques ion esea che s asked conce ned a po en ial pa e n (uni e sal s. speci ic) o SEs p esence in AD- de i ed S. au eus. I has been known ha 54–71.25% o S. au eus isola es indica ed he p esence o SE genes among AD pa ien s (Mempel e al., 2003;Nada e al., 2012). Fu he mo e, a me a- analysis o 95 s udies indica ed ha he a e o oxins p oducing S. au eus on he lesional skin luc ua ed be ween 31.5 and 80% (To é e al., 2016), and was highe han in heal hy con ols. The dis ibu ion o SE genes, howe e , a ied om one s udied popula ion o ano he : in Ko ean popula ion sea and ss -1 we e he mos common oxin genes (Kim e al., 2009;Na e al., 2012); in Ge many, whe eas one s udy showed ha seb (38%) and ss - 1(23%) oxin genes we e he mos p e alen , and sea was no de ec ed (Zollne e al., 2000), o he e ealed ha sea and sed we e mos commonly de ec ed (B eue e al., 2002). All SEs p oduc ion pa e ns om adul AD pa ien s a e summa ized in Table 2. In he s udies o Taiwanese child en wi h AD, he mos equen oxin gene was seb (87%), ollowed by sec (9%), ss -1 (9%), sea (4%), seg/sei (4%), and seh (4%). The sed oxin gene was no iden i ied in a opic child en, whe eas i was p edominan in heal hy child en. I is wo h o men ion, howe e , ha only he MRSA popula ion was s udied (Lo e al., 2010). In England, he mos p e alen oxins we e sec (25% om he skin; 11% om he nose), seg (21% om he skin; 17% om he nose), and sei (21% om he skin; 17% om he nose). Mos cases ep esen ed he same s ains in he nose and skin (A kw igh e al., 2001). In Spain, hla and hlg/hlgV (26, 100%), hlb (17, 65.5%), lukDE (25, 96.1%), ss -1 (13, 50%), au (11, 42.3%), cna (10, 38.5%), e a (4, 15.4%), and sec (2, 7.7%) we e he i ulence genes de ec ed in cu aneous isola es o child en wi h AD (Gilabe e e al., 2015). The obse ed a ia ions in SEs dis ibu ion pa e ns in di e en esea ch and di e en AD popula ions indica e geog aphical dependence. All SEs p oduc ion pa e ns om AD child en a e summa ized in Table 1. In e es ingly, in some s udies based on popula ions o bo h child en and adul s, he mos equen ly de ec ed genes we e no classical oxins ound in 38% o AD-de i ed s ains, bu en e o oxin gene clus e (egc), which consis ed o seg, sei, sek, sem, sen, and seo (Mempel e al., 2003). S udies on he AD coho om Singapo e indica ed ha he mos p e alen SEs we e seb (42%), egc (32%), and seh (29%). In e es ingly, Chiu e al. p oposed ha pa ien s wi h a mode a e ype o AD we e mo e likely o be colonized by S. au eus possessing s aphylococcal en e o oxin B (seb) han pa ien s wi h a se e e ype o AD (Chiu e al., 2009). Ne e heless, ano he dis ibu ion pa e n o oxins was obse ed in Po uguese AD pa ien s, whe e 76% o he examined S. au eus s ains we e SE-posi i e, mainly o SEls:sel-m and sel-n (71.4%), ollowed by sel-o and seg (66.7%) and sea and sel-l we e less equen (29% and 33%, espec i ely) (Soa es e al., 2013). In he Egyp ian coho , he mos p e alen gene om he S. au eus s ains isola ed om he lesional skin o AD pa ien s was seb, ollowed by sec and ss -1,sea and sed (Nada e al., 2012). All SEs gene p esence pa e ns om he mixed g oups o AD pa ien s a e summa ized in Table 3. I is no uncommon ha AD-de i ed s ains o S. au eus can p oduce mo e han a single en e o oxin (Schlie e e al., 2008; Na e al., 2012), and a signi ican ly highe amoun s (Schlie e e al., 2008). The o e all pic u e is e en mo e complex when F on ie s in Mic obiology | www. on ie sin.o g 9Janua y 2021 | Volume 11 | A icle 567090 micb-11-567090 Decembe 31, 2020 Time: 11:20 # 16 Ogonowska e al. S aphylococcus au eus in A opic De ma i is Ca oll, C. L., Balk ishnan, R., Feldman, S. R., Fleische , A. B., and Manuel, J. C. (2005). The bu den o a opic de ma i is: impac on he pa ien , amily, and socie y. Pedia . De ma ol. 22, 192–199. doi: 10.1111/j.1525-1470.2005.22303.x Chan, A., and Mau o, T. (2011). 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This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) and he copy igh owne (s) a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. F on ie s in Mic obiology | www. on ie sin.o g 19 Janua y 2021 | Volume 11 | A icle 567090