응용 과학 Applied Science/건강, 의료 Health

가려움증, 황색포도상구균, S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis

Jobs 9 2023. 12. 2. 14:32
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가려움증은 습진이나 아토피 피부염 같은 질환을 더욱 괴롭게 만드는 요인이다. 많은 이들이 가려움증을 참지 못해 피부를 긁고, 이는 피부염을 더 악화시킨다.그러나 구체적으로 무엇이 어떻게 가려움증을 유발하는지는 그동안 정확히 규명되지 않았다. 전문가들은 대체로 피부에 생긴 염증이 동반되는 증상이나 면역 반응의 결과로 여겼다. 피부질환에 염증과 면역 반응을 억제하는 스테로이드 연고를 쓰는 이유가 여기에 있다.

 

미국 하버드대 의대 연구진이 쥐와 인간 세포 실험을 통해 호흡기관과 피부에 주로 서식하는 황색포도상구균(MRSA)이 피부의 신경세포를 자극해 가려움증을 유발한다는 사실을 밝혀내 국제학술지 ‘셀’에 발표했다. 황색포도상구균은 식중독의 원인 물질이기도 하다.연구진은 황색포도상구균이 염증과 상관 없이 긁고 싶은 충동을 일으키는 분자 연쇄 반응을 유발한다고 밝혔다.과학자들은 습진 환자의 피부에 황색포도상구균이 서식하는 경우가 많다는 사실을 오래전부터 알고 있었지만, 이 박테리아가 어떤 역할을 하는지는 분명하게 알지 못했다. 이번 연구로 그동안 피부 염증이 원인으로 생각했던 것이 사실은 피부에 염증이 생기면 피부 미생물의 균형이 깨지면서 황색포도상구균이 번성하는 경우가 많기 때문이라는 사실이 드러나게 됐다.

박테리아 효소가 잠자는 ‘가려움 단백질’ 깨워

 

연구진은 실험에서 우선 생쥐 피부에 황색포도상구균을 노출시켰다. 그러자 가려움증을 느낀 생쥐들은 피부를 긁기 시작했고 피부를 긁는 행동은 날이 갈수록 심해졌다. 그에 따라 피부 손상이 악화돼 가려움증을 느끼는 부위도 점차 넓어졌다. 나중엔 가려움증을 유발하지 않는 약한 자극에도 과민 반응을 보였다. 알로크네시스(alloknesis)라고 부르는 이런 과민 반응은 만성 피부 질환 환자에게서 흔히 나타나는 현상이다.연구진은 황색포도상구균이 가려움증을 유발하는 메카니즘을 확인하기 위해, 이 미생물이 피부에 닿으면 방출한다고 알려진 효소 단백질 10가지 각각에 대한 쥐의 반응을 지켜봤다.박테리아 유전자를 조작해 효소를 하나씩 제거하면서 확인한 결과, V8이라는 단백질 분해 효소가 가려움증을 유발한다는 사실이 드러났다. 연구진은 이어 아토피 피부염을 앓고 있는 사람 피부에서 다른 사람보다 황색포도상구균이 더 많으며, V8 수치도 더 높다는 걸 확인했다.분석 결과, V8 효소는 피부 신경세포의 PAR1이라는 단백질을 활성화해 가려움증을 유발하는 것으로 나타났다. 척수에서 유래한 이 단백질은 피부가 느끼는 촉감이나 열, 통증, 가려움증 같은 감각 신호를 뇌로 전달해주는 물질이다.이 단백질은 평소엔 휴면 상태이지만 V8 같은 특정 효소를 만나면 깨어난다. 연구진은 V8 효소가 이 단백질의 한 쪽 끝을 잘라내는 방식으로 단백질을 휴면에서 깨운다고 밝혔다. 생쥐 실험에서 이 단백질이 활성화하면 뇌가 가려움증으로 인식하는 신호가 시작되는 것으로 나타났다. 인간 신경세포를 이용한 실험에서도 신경세포는 V8 효소에 같은 반응을 보였다.

2만배율로 본 황색포도상구균의 주사전자현미경 사진. 참조 막대는 1㎛(100만분의 1m). 위키미디어 코먼스

스테로이드 연고 안듣는 피부염 치료에 희소식

 

 

연구를 이끈 하버드의대의 아이작 추 교수(면역학)는 “이번 연구는 가려움증의 이면에 있는 완전히 새로운 메카니즘을 확인한 것”이라며 “그것은 바로 만성 아토피성 피부염을 앓고 있는 거의 모든 환자들한테서 발견되는 황색포도상구균”이라고 말했다.흥미로운 건 그동안 피부 알레르기나 가려움증을 유발하는 것으로 알려진 비만 세포, 호염기구 같은 면역 세포는 이번 실험에서 박테리아에 노출된 후에도 가려움증을 유발하지 않았다는 점이다.연구진은 황색포도상구균이 활성화하는 단백질 PAR1이 혈액 응고에도 관여한다는 점에 착안해 치료 방법도 찾아냈다. 황색포도상구균에 노출시킨 생쥐에게 항응고제를 바르자 증상이 빠르게 개선되는 걸 확인했다.연구진은 “현재 혈전 예방용으로 쓰이는 항응고제(PAR1 차단제)를 용도를 바꿔 가려움증 치료에도 쓸 수 있을 것”이라고 밝혔다. 연구진은 이번 연구가 아토피 피부염, 결절성 피부염, 건선 등 피부 미생물 군집의 불균형과 관련된 다양한 질환에서 발생하는 가려움증을 치료하기 위한 알약이나 연고제 개발에 유용한 정보가 될 것으로 기대했다.이번 연구는 그동안 베일에 싸여 있던 가려움증의 메카니즘을 확인했다는 점에서 큰 의미가 있다. 연구에 참여하지 않은 존스홉킨스의대 네이선 아처 교수(피부과학)는 ‘엔비시뉴스’에 “이번 연구는 염증 반응과 가려움증 반응을 분리해냈다”며 “스테로이드 연고 같은 치료법이 잘 듣지 않는 피부염 환자들을 치료하는 데 중요한 단서가 될 수 있다”고 말했다.그러나 이번 연구가 황색포도상구균이 가려움증의 유일한 원인균이라는 걸 말하는 것은 아니다.연구진은 “곰팡이, 바이러스, 박테리아를 포함한 많은 미생물이 가려움증을 동반한다”며 이들 미생물에 대해서도 어떻게 가려움·증을 유발하는지 연구할 계획이라고 밝혔다.이번 연구는 또 ‘미생물은 왜 가려움증을 유발할까’라는 좀 더 근본적인 질문을 제기한다. 진화론 측면에서 가려움증을 유발해 박테리아가 얻는 건 뭘까?연구진은 가려움증에 따른 숙주의 긁기 행동이 미생물의 확산 또는 번식에 유리하게 작용할 가능성이 있다고 말했다. 연구진은 결핵 박테리아가 미주신경을 자극해 기침을 유발함으로써 다른 숙주로 확산해가는 경우를 비슷한 사례로 들었다.“가려워서 긁는 행위는 왜 일어날까? 우리에게 도움이 될까, 아니면 미생물에게 도움이 될까?” 논문 제1저자인 리웬 덩 박사후연구원은 “앞으로 후속 연구를 통해 밝혀내야 할 부분”이라고 말했다. 

 

 

 

 

Highlights

  • •
    S. aureus induces itch and scratch damage with epicutaneous skin exposure
  • •
    V8 protease (SspA) is necessary and sufficient for itch during S. aureus exposure
  • •
    S. aureus V8 activates mouse and human sensory neurons through PAR1
  • •
    PAR1 deficiency or blockade abrogates S. aureus-induced itch and skin damage

Summary

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

Graphical abstract

Keywords

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Article info

Publication history

Published: November 22, 2023
Accepted: October 18, 2023
Received in revised form: August 20, 2023
Received: December 22, 2022
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