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人类OTULIN单倍体不足损害细胞对葡萄球菌α-毒素的细胞内在免疫力
作者:小柯机器人 发布时间:2022/5/22 22:15:05

美国洛克菲勒大学Jean-Laurent Casanova、András N. Spaan等研究人员合作发现,人类OTULIN单倍体不足损害细胞对葡萄球菌α-毒素的细胞内在免疫力。相关论文于2022年5月19日在线发表在《科学》杂志上。

研究人员描述了由5p染色体上一个基因编码的线性去泛素酶OTULIN的单倍体功能不全的患者。患者出现危及生命的坏死发作,通常由金黄色葡萄球菌感染引发。这种疾病与5p-(Cri-du-Chat)染色体缺失综合征的患者有相似之处。OTULIN单倍体功能不足导致皮肤成纤维细胞中线性泛素的积累,但TNF-受体NF-κB-信号传导保持不变。血液白细胞亚群不受影响。

OTULIN依赖性的caveolin-1在皮肤成纤维细胞中的积累(但不是白细胞),进而促进了葡萄球菌毒力因子α-毒素造成的细胞毒性损伤。自然诱发的针对α-毒素的抗体导致了不完全的临床渗透性。人类OTULIN单倍体功能不足是威胁生命的葡萄球菌疾病的基础,因为它破坏了非白细胞细胞内对α-毒素的细胞内在免疫力。

据悉,感染金黄色葡萄球菌后个体间临床变异的分子基础尚不清楚。

附:英文原文

Title: Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin

Author: András N. Spaan, Anna-Lena Neehus, Emmanuel Laplantine, Frederik Staels, Masato Ogishi, Yoann Seeleuthner, Franck Rapaport, Keenan A. Lacey, Erika Van Nieuwenhove, Maya Chrabieh, David Hum, Mélanie Migaud, Araksya Izmiryan, Lazaro Lorenzo, Tatiana Kochetkov, Dani A. C. Heesterbeek, Bart W. Bardoel, Ashley L. DuMont, Kerry Dobbs, Solenne Chardonnet, Sren Heissel, Timour Baslan, Peng Zhang, Rui Yang, Dusan Bogunovic, Herman F. Wunderink, Pieter-Jan A. Haas, Henrik Molina, Griet Van Buggenhout, Stanislas Lyonnet, Luigi D. Notarangelo, Mikko R. J. Seppnen, Robert Weil, Gisela Seminario, Héctor Gomez-Tello, Carine Wouters, Mehrnaz Mesdaghi, Mohammad Shahrooei, Xavier Bossuyt, Erdal Sag, Rezan Topaloglu, Seza Ozen, Helen L. Leavis, Maarten M. J. van Eijk, Liliana Bezrodnik, Lizbeth Blancas Galicia, Alain Hovnanian, Aude Nassif, Brigitte Bader-Meunier, Bénédicte Neven, Isabelle Meyts, Rik Schrijvers, Anne Puel, Jacinta Bustamante, Ivona Aksentijevich, Daniel Kastner, Victor J. Torres, Stéphanie Humblet-Baron, Adrian Liston, Laurent Abel, Bertrand Boisson, Jean-Laurent Casanova

Issue&Volume: 2022-05-19

Abstract: The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients present episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but TNF-receptor NF-κB-signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts—but not leukocytes—facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in non-leukocytic cells.

DOI: abm6380

Source: https://www.science.org/doi/10.1126/science.abm6380

 

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037