포도알구균의 외독소 유전자 분석과 그 외독소가 개 아토피 피부염에 미치는 영향

Profile of the Staphylococcal Exotoxin Gene and its Relation with Canine Atopic Dermatitis

  • 남의화 (서울대학교 수의과대학.수의과학연구소) ;
  • 정태호 (서울대학교 수의과대학.수의과학연구소) ;
  • 김지현 (서울대학교 수의과대학.수의과학연구소) ;
  • 박설희 (서울대학교 수의과대학.수의과학연구소) ;
  • 김효은 (서울대학교 수의과대학.수의과학연구소) ;
  • 윤화영 (서울대학교 수의과대학.수의과학연구소) ;
  • 채준석 (서울대학교 수의과대학.수의과학연구소) ;
  • 박용호 (서울대학교 수의과대학.수의과학연구소) ;
  • 황철용 (서울대학교 수의과대학.수의과학연구소)
  • Nam, Eui-Hwa (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University) ;
  • Chung, Tae-Ho (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University) ;
  • Kim, Ji-Hyun (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University) ;
  • Park, Seol-Hee (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University) ;
  • Kim, Hyo-Eun (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University) ;
  • Youn, Hwa-Young (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University) ;
  • Chae, Joon-Seok (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University) ;
  • Park, Yong-Ho (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University) ;
  • Hwang, Cheol-Yong (College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University)
  • 심사 : 2011.04.04
  • 발행 : 2011.04.30

초록

포도알구균은 아토피 피부염 환자의 피부병변에서 가장 많이 발견되는 세균으로, 이들 균집락의 정도는 사람 아토피 피부염의 임상증상 악화요인으로 알려져있다. 이에 본 연구에서는 개 아토피 피부염 환자의 피부에서 포도알구균의 존재를 확인하고, 이들 균주가 생산하는 외독소 유형을 분석하여 개 아토피 피부염 환자의 임상증상과의 연관성을 알아보았다. 79마리의 개 아토피 피부염 환자 중 91.1%인 72마리에서 포도알구균이 검출되었으며, 이 중 62마리에서 Staphylococcus pseudintermedius가 가장 높은 빈도로 확인되었다. 외독소 유전자 분석에서는 69.4%인 50마리에서 1가지 이상의 외독소 유전자를 포함하였고, 이들 중 56%인 28마리에서 2가지 이상의 다른 외독소 유전자를 가지고 있는 것으로 나타났다. 개 아토피 피부염 환자를 포도알구균의 존재 유무에 따라 분류하였을 때, 임상증상 점수의 차이에 통계적인 의미는 없었지만 (P=0.598), 외독소 유무에 따라 임상증상 점수를 비교하였을 때는 의미있는 차이를 보였다 (P=0.028). 또한 외독소 유형에 따라 분류하였을 때 외독소 중 SED와 exfoliative toxins에서 임상증상에 의미있는 차이를 보였으며 (P<0.05), 외독소 유무에 따라 분류하였을 때는 임상증상 점수 중 특히 발적과 구진/농포에서 의미있는 차이를 보였다 (P<0.05). 이와 같은 결과를 통해 개 아토피 피부염에서 포도얄구균이 생산하는 외독소가 개 아토피 피부염의 증상악화와 관련이 있는 것으로 사료된다.

Staphylococcus spp. is one of the most common bacteria isolated from the lesions of atopic dermatitis (AD) in humans, and their colonization is known to be a possible trigger factor of clinical signs. The aim of this study was to determine the prevalence of Staphylococcus spp. in canine AD (CAD), the types of exotoxins present, and their relation with the clinical severity of CAD. From 79 dogs with AD, 72 samples of Staphylococcus spp. were isolated (91.1%), and 65 (90.3%) were confirmed as Staphylococcus pseudintermedius. Concerning the profile of the exotoxin gene, 50 isolates (69.4%) contained at least one exotoxin gene, and 28 isolates (56%) were found to contain more than 2 different exotoxins. There was a significant difference in clinical severity with the presence of staphylococcal exotoxins (P=0.028), whereas no correlation was found with the presence of Staphylococcus spp. (P=0.598). The clinical severity of CAD increased only in relation to staphylococcal enterotoxin D (SED) and exfoliative toxins (P<0.05). Some clinical evaluation criteria (erythema, papule/pustule) were correlated with the presence of the exotoxin gene (P<0.05). This study showed that the high prevalence of Staphylococcus spp. and staphylococcal exotoxins in lesions from dogs with AD may be regarded as an important trigger factor for exacerbation of the clinical signs of CAD.

키워드

참고문헌

  1. Adachi Y, Akamatsu H, Horio T. The effect of antibiotics on the production of superantigen from Staphylococcus aureus isolated from atopic dermatitis. J Dermatol Sci 2002; 28: 76-83. https://doi.org/10.1016/S0923-1811(01)00143-8
  2. Adesiyun AA, Usman B. Isolation of enterotoxigenic strains of staphylococci from dogs. Vet Microbiol 1983; 8:459-468 https://doi.org/10.1016/0378-1135(83)90040-8
  3. Baker BS. The role of microorganisms in atopic dermatitis. Clin Exp Immunol 2006; 144: 1-9. https://doi.org/10.1111/j.1365-2249.2005.02980.x
  4. Bannoehr J, Franco A, lurescia M, Battisti A, Fitzgerald J. Molecular diagnostic identification of Staphylococcus pseudintermedius. J Clin Microbiol 2008; 47: 469-471
  5. Becker K, Keller B, Von Eiff C, Bruck M, Lubritz G, Etienne J, Peters G Enterotoxigenic potential of Staphylococcus intermedius. Appl Environ Microbiol. 2001; 67: 5551. https://doi.org/10.1128/AEM.67.12.5551-5557.2001
  6. Breuer K, Haussler S, Kapp A, Werfel T. Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis. Br J Dermatol. 2002; 147: 55-61. https://doi.org/10.1046/j.1365-2133.2002.04872.x
  7. Breuer K, Werfel T, Kapp A. Staphylococcal Exotoxins as Trigger Factors of Atopic Dermatitis. New Trends in Allergy 2002; V: 145.
  8. Bunikowski R, Mielke M, Skarabis H, Worm M, Anagnostopoulos I, Kolde G, Wahn U, Renz H. Evidence for a diseasepromoting effect of Staphylococcus aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol. 2000; 105: 814-819 https://doi.org/10.1067/mai.2000.105528
  9. Burkett G, Frank L. Comparison of production of Staphylococcus intermedius exotoxin among clinically normal dogs, atopic dogs with recurrent pyoderma, and dogs with a single episode of pyoderma. J Am Vet Med Assoc. 1998; 213: 232.
  10. Campbell D, Kemp A. Proliferation and production of interferon- gamma (IFN-$\gamma$) and IL-4 in response to Staphylococcus aureus and Staphylococcal superantigen in childhood atopic dermatitis. Clin Exp lmmunol. 1997; 107: 392. https://doi.org/10.1111/j.1365-2249.1997.278-ce1172.x
  11. Campbell D, Kemp A. Production of antibodies to staphylococcal superantigens in atopic dermatitis. Arch Dis Child. 1998; 79: 400. https://doi.org/10.1136/adc.79.5.400
  12. Cardona I, Cho S, Leung D. Role of bacterial superantigens in atopic dermatitis: implications for future therapeutic strategies. Am J Clin Dermatol. 2006; 7: 273-279. https://doi.org/10.2165/00128071-200607050-00001
  13. Davison S, AlIen M, Vaughan R, Barker J. Staphylococcal toxin-induced T cell proliferation in atopic eczema correlates with increased use of superantigen-reactive V -chains in cutaneous Iymphocyte-associated antigen (CLA)-positive Iymphocytes. Clin Exp Immunol. 2000; 121: 181. https://doi.org/10.1046/j.1365-2249.2000.01270.x
  14. De Benedetto A, Agnihothri R, McGirt L, Bankova L, Beck L. Atopic Dermatitis: A Disease Caused by Innate lmmune Defects&quest. J Invest Dermatol. 2009; 129: 14-30. https://doi.org/10.1038/jid.2008.259
  15. DeBoer DJ, Hillier A. The ACVD task force on canine atopic dermatitis (XV): fundamental concepts in clinical diagnosis. Vet Immunol Immunopathol. 2001; 81: 271-276. https://doi.org/10.1016/S0165-2427(01)00312-9
  16. DeBoer DJ, Marsella R. The ACVD task force on canine atopic dennatitis (XII): the relationship of cutaneous infections to the pathogenesis and clinical course of canine atopic dermatitis. Vet Immunol Immunopathol. 2001; 81: 239-249. https://doi.org/10.1016/S0165-2427(01)00345-2
  17. DeBoer DJ, Hillier A. The ACVD task force on canine atopic dermatitis (XVI): laboratory evaluation of dogs with atopic dermatitis with serum-based "allergy" tests. Vet Immunol Immunopathol. 2001; 81: 277-287. https://doi.org/10.1016/S0165-2427(01)00304-X
  18. Dinges M, Orwin P, Schlievert P. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev. 2000; 13: 16. https://doi.org/10.1128/CMR.13.1.16-34.2000
  19. Fazakerley J, Nuttall T, Sales D, Schmidt V, Carter S, Hart C, McEwan N. Staphylococcal colonization of mucosal and lesional skin sites in atopic and healthy dogs. Vet dermatol. 2009; 20: 179-184. https://doi.org/10.1111/j.1365-3164.2009.00745.x
  20. Hendricks A, Schuberth H, Schueler K, Lloyd D. Frequency of superantigen-producing Staphylococcus intermedius isolates from canine pyoderma and proliferation-inducing potential of superantigens in dogs. Res vet Sci. 2002; 73: 273-277. https://doi.org/10.1016/S0034-5288(02)00107-8
  21. Hirooka E, Muller E, Freita, J, Vicente E, Yoshimoto Y, Bergdoll M. Enterotoxigenicity of Staphylococcus of Staphylococcus intermedius of canine origin. Int J Food Microbiol. 1988; 7: 185-191. https://doi.org/10.1016/0168-1605(88)90036-0
  22. Hoeger P, Lenz W, Boutonnier A, Fournier J. Staphylococcal skin colonization in children with atopic dermatitis: prevalence, persistence, and transmission of toxigenic and nontoxignic strains. J Infect Dis. 1992; 165: 1064-1068. https://doi.org/10.1093/infdis/165.6.1064
  23. Hwang SY, Kim SH, Jang EJ, Kwon NH, Park YK, Koo HC, Jung of the Staphylococcus aureus superantigen and its applcation to raw meat isolates in Korea. Int J Food Microbiol. 2007. 117: 99-105. https://doi.org/10.1016/j.ijfoodmicro.2007.02.013
  24. Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol. 1991; 96: 523-526. https://doi.org/10.1111/1523-1747.ep12470233
  25. Khobragade K. Efficacy and safety of combination ointment" fluticasone propionate 0.005% plus mupirocin 2.0%" for the treatment of atopic dermatitis with clinical suspicion of secondary bacterial infection: An open label uncontrolled study. Indian J Dermatol Venerol. 2005; 71: 91. https://doi.org/10.4103/0378-6323.13991
  26. Krakauer T, Stiles BG. Staphylococcal Enterotoxins, Toxíc Shock Syndrome TIxin-I, and Streptococcal Pyrogenic Exotoxins: Some Basic Biology of Bacterial Superantigens. Recent Res Dev Infect Immun. 2003; 1: 1-27.
  27. Leung DY, Harbeck R, Bina P, Reiser RF, Yang E, Norris DA, Hanitin JM, Sampson HA. Prcsence of IgE antibodies to staphylococcaI exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens. J Clin Invest. 1993; 92: 1374. https://doi.org/10.1172/JCI116711
  28. Lin YT, Wang CT, Chiang BL. Role of bacterial pathogens in atopic dermatitis. Clin Rev Allergy Immunol. 2007; 33: 167-177. https://doi.org/10.1007/s12016-007-0044-5
  29. McCormick JM, Yarwood, JM and Schlievert PM. Toxic shock syndrome and bacterial superantigens : An Update. Annu Rev Microbiol. 2001; 55: 77-104. https://doi.org/10.1146/annurev.micro.55.1.77
  30. McFadden JP, Noble WC, Carnp RDR. Superantigenic exotoxin-secreting potential of staphylococci isolated from atopic eczematous skin. Br J Dermatol. 2006; 128: 631-632.
  31. McGirt LY, Beck LA. Innate immune defects in atopic dermatitis. J Allergy Clin lmmunol. 2006; 118: 202-208. https://doi.org/10.1016/j.jaci.2006.04.033
  32. Mehrotra M, Wang G, Johnson WM. Multiplex PCR for detection of genes for Staphylococcus aureus enterotoxins, exfoliative toxins, toxic shock syndrome toxin 1, and methicillin resistance. J Clin Microbiol. 2000; 38: 1032.
  33. Monday SR, Vath GM, Fepens WA, Deobald C, Rago JV, Gahr PJ, Monie DD, landolo JJ, Chapes SK, Davis WC. Unique superantigen activity of staphylococcal exfoliative toxins. J lmmunol. 1999; 162: 4550.
  34. Morishita Y, Tada J, Sato A, Toi Y, Kanzaki H. Akiyama H, Arata J. Possible influences of Staphylococcus aureus on atopic dermatitis-the colonizing features and the effects of staphylococcal enterotoxins. Clin Exp Allergy. 2001; 29: 1110-1117.
  35. Nomura I, Tanaka K, Tomita H, Katsunuma T, Ohya Y, Ikeda N, Takeda T, Saito H, Akasawa A. Evaluation of the staphylococcal exotoxins and their specific IgE in childhood atopic dermatitis. J Allergy Clin Immunol. 1999; 104: 441-446. https://doi.org/10.1016/S0091-6749(99)70390-8
  36. Olivry T, Rivierre C, Jackson H, Murphy K, Davidson G, Sousa C. Cyclosporine decreases skin lesions and pruritus in dogs with atopic dermatitis: a blinded randomized prednisolone-controlled trial. Vet Dermatol. 2002; 13: 77-87 https://doi.org/10.1046/j.1365-3164.2002.00283.x
  37. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo R, Leung D. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002; 347: 1151. https://doi.org/10.1056/NEJMoa021481
  38. Ong PY, Patel M, Ferdman RM, Dunaway T, Church J. Association of staphylococcal superantigen-specific immunoglobulin E with mild and moderate atopic dermatitis. J Pediatr. 2008; 153: 803-806. https://doi.org/10.1016/j.jpeds.2008.05.047
  39. Raus J, Love DN. Characterization of coagulase-positive Staphylococcus intermedius and Staphylococcus aureus isolated from veterinary clinical specimens. J Clin Microbiol. 1983; 18: 789.
  40. Ricci G, Dondi A, Patrizi A. Staphylococcus aureus overinfection in atopic dermatitis. J Pediatr Infect Dis. 2008; 3: 83-90.
  41. Roll A, Cozzio A, Fischer B, Schmid-Grendelmeier P. Microbial colonization and atopic dermatitis. Currt Opin Allergy Clin Immunol. 2004; 4: 373. https://doi.org/10.1097/00130832-200410000-00008
  42. Saloga J, Leung DYM, Reardon C, Giomo R, Born W, Gelfand E. Cutaneous exposure to the superantigen staphylococcal enterotoxin B elicits a T-cell-dependent inflammatory response. J Invest Dermatol. 1996; 106: 982-988 https://doi.org/10.1111/1523-1747.ep12338479
  43. Schnopp C, Ring J, Mempel M. The role of antibacterial therapy in atopic eczema. Expert Opin Pharmacother. 2010; 11: 929-936. https://doi.org/10.1517/14656561003659992
  44. Solanki LS, Srivastava N. Singh S. Superantigens: a brief review with special emphasis on dermatologic disease. Dermatol Online J. 2008; 14: 3.
  45. Yoon JW, Lee GJ, Lee SY, Park C, Yoo JH, Park HM. Prevalence of genes for enterotoxins, toxic shock syndrome toxin 1 and exfoliative toxin among clinical isolates of Staphylococcus pseudintermedius from canine origin. Vet Dermatol. 2010; 21: 484-489 https://doi.org/10.1111/j.1365-3164.2009.00874.x