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DOI 10.1126/science.abm6380

Медицинская библиотека · Science (New York, N.Y.) · 2022

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

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

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Аннотация

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 suffer from 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 tumor necrosis factor receptor-mediated nuclear factor 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 nonleukocytic cells.

Для цитирования: Spaan András N, Neehus Anna-Lena, Laplantine Emmanuel, Staels Frederik, Ogishi Masato, Seeleuthner Yoann, Rapaport Franck, Lacey Keenan A, Van Nieuwenhove Erika, Chrabieh Maya, Hum David, Migaud Mélanie, Izmiryan Araksya, Lorenzo Lazaro, Kochetkov Tatiana, Heesterbeek Dani A C, Bardoel Bart W, DuMont Ashley L, Dobbs Kerry, Chardonnet Solenne, Heissel Søren, Baslan Timour, Zhang Peng, Yang Rui, Bogunovic Dusan, Wunderink Herman F, Haas Pieter-Jan A, Molina Henrik, Van Buggenhout Griet, Lyonnet Stanislas, Notarangelo Luigi D, Seppänen Mikko R J, Weil Robert, Seminario Gisela, Gomez-Tello Héctor, Wouters Carine, Mesdaghi Mehrnaz, Shahrooei Mohammad, Bossuyt Xavier, Sag Erdal, Topaloglu Rezan, Ozen Seza, Leavis Helen L, van Eijk Maarten M J, Bezrodnik Liliana, Blancas Galicia Lizbeth, Hovnanian Alain, Nassif Aude, Bader-Meunier Brigitte, Neven Bénédicte, Meyts Isabelle, Schrijvers Rik, Puel Anne, Bustamante Jacinta, Aksentijevich Ivona, Kastner Daniel L, Torres Victor J, Humblet-Baron Stéphanie, Liston Adrian, Abel Laurent, Boisson Bertrand, Casanova Jean-Laurent. Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.. Science (New York, N.Y.). 2022. DOI: 10.1126/science.abm6380.

Предметные рубрики MeSH

Bacterial ToxinsCri-du-Chat SyndromeEndopeptidasesHaploinsufficiencyHemolysin ProteinsHost-Pathogen InteractionsHumansImmunity, CellularNecrosisStaphylococcal InfectionsStaphylococcus aureus
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