Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin

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; Søren 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. Seppänen; 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 L. Kastner; Victor J. Torres; Stéphanie Humblet-Baron; Adrian Liston; Laurent Abel; Bertrand Boisson; Jean Laurent Casanova

doi:10.1126/science.abm6380

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin

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 ChardonnetSøren 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. Seppänen, 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 L. Kastner, Victor J. Torres, Stéphanie Humblet-Baron, Adrian Liston, Laurent Abel, Bertrand Boisson, Jean Laurent Casanova

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

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 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 kB 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 a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.

Original language	English
Article number	eabm6380
Journal	Science
Volume	376
Issue number	6599
DOIs	https://doi.org/10.1126/science.abm6380
Publication status	Published - 17 Jun 2022

Keywords

Bacterial Toxins/immunology
Cri-du-Chat Syndrome/genetics
Endopeptidases/genetics
Haploinsufficiency/genetics
Hemolysin Proteins/immunology
Host-Pathogen Interactions/genetics
Humans
Immunity, Cellular/genetics
Necrosis
Staphylococcal Infections/genetics
Staphylococcus aureus

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10.1126/science.abm6380

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Spaan, A. N., Neehus, A. L., Laplantine, E., Staels, F., Ogishi, M., Seeleuthner, Y., Rapaport, F., Lacey, K. A., Van Nieuwenhove, E., Chrabieh, M., Hum, D., Migaud, M., Izmiryan, A., Lorenzo, L., Kochetkov, T., Heesterbeek, D. A. C., Bardoel, B. W., DuMont, A. L., Dobbs, K., ... Casanova, J. L. (2022). Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin. Science, 376(6599), Article eabm6380. https://doi.org/10.1126/science.abm6380

@article{72c5b7f645614c8885a059fc0b37d240,

title = "Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin",

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 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 kB 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 a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.",

keywords = "Bacterial Toxins/immunology, Cri-du-Chat Syndrome/genetics, Endopeptidases/genetics, Haploinsufficiency/genetics, Hemolysin Proteins/immunology, Host-Pathogen Interactions/genetics, Humans, Immunity, Cellular/genetics, Necrosis, Staphylococcal Infections/genetics, Staphylococcus aureus",

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

note = "Funding Information: This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (UL1TR001866 to The Rockefeller University), the Sackler Center for Biomedicine and Nutrition at the Center for Clinical and Translational Science at The Rockefeller University and the Shapiro-Silverberg Fund for the Advancement of Translational Research (to A.N.S.), NIH P01AI061093 (to J.-L.C.), the Square Foundation, the French National Research Agency (ANR-10-IAHU-01, ANR-21-CE17-0014-03, ANR 14-CE15-0009-01, and ANR-15-CE17-0014), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (EQU201903007798), the Howard Hughes Medical Institute, the St. Giles Foundation, The Rockefeller University, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), the Paris Cit{\'e} University, the Laura and Isaac Perlmutter Cancer Center and the National Institutes of Health/National Cancer Institute (P30CA016087 to NYU Langone{\textquoteright}s Rodent Genetic Engineering Laboratory), the Bettencourt Schueller Foundation and the International PhD program of the Imagine Institute (to A.-L.N.), the David Rockefeller Graduate Program (to M.O.), the New York Hideyo Noguchi Memorial Society (to M.O.), the Funai Foundation for Information Technology (to M.O.), the Honjo International Scholarship Foundation (to M.O.), the Cystic Fibrosis Foundation Postdoctoral Research Fellowship award (LACEY19FO to K.A.L.), the William C. and Joyce C. O{\textquoteright}Neil Charitable Trust (to T.B.), the Memorial Sloan Kettering Single Cell Sequencing Initiative (to T.B.), the Hospital Research Funds at the Pediatric Research Center at the Helsinki University Hospital (to M.R.J.S.), and the Foundation for Pediatric Research of Finland (to M.R.J.S.). C.W. serves as a member of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (739543). The work was supported in part by the ERC Start grant IMMUNO (ERC-2010-StG_20091118 to A.L.), the VIB Grand Challenges (to A.L., S.H.-B., and R.S.), the KU Leuven BOFZAP start-up grant (to S.H.-B.), National Fund for Scientific Research senior clinical investigator fellowships (1805518N to R.S. and G0B5120N to I.M.), National Fund for Scientific Research grants (G0E8420N and G0C8517N to I.M.), a KU Leuven C1 grant (to I.M.), and the ERC Start grant MORE2ADA2 (ERC-2020-StG_948959 to I.M.). I.M. is a member of ERN-RITA. D.B. is supported by the NIH (R01 AI148963) and a founder of Lab11 Therapeutics Inc. The S. aureus work in the Torres laboratory is funded by the NIH (R01 AI099394, R01 AI105129, R01 AI121244, R01 AI137336, and R01 AI140754 to V.J.T.). V.J.T. is a Burroughs Wellcome Fund Investigator in the pathogenesis of infectious diseases. A.N.S. was supported in part by the European Union{\textquoteright}s Horizon 2020 Research and Innovation Program (Marie Sk{\l}odowska-Curie grant 789645), the Dutch Research Council Talent Program (NWO Rubicon grant 019.171LW.015, partially nonstipendiary), and the European Molecular Biology Organization (EMBO Long-Term Fellowship grant ALTF 84-2017, nonstipendiary). Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = jun,

day = "17",

doi = "10.1126/science.abm6380",

language = "English",

volume = "376",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6599",

}

Spaan, AN, Neehus, AL, Laplantine, E, Staels, F, Ogishi, M, Seeleuthner, Y, Rapaport, F, Lacey, KA, Van Nieuwenhove, E, Chrabieh, M, Hum, D, Migaud, M, Izmiryan, A, Lorenzo, L, Kochetkov, T, Heesterbeek, DAC, Bardoel, BW, DuMont, AL, Dobbs, K, Chardonnet, S, Heissel, S, Baslan, T, Zhang, P, Yang, R, Bogunovic, D, Wunderink, HF, Haas, PJA, Molina, H, Van Buggenhout, G, Lyonnet, S, Notarangelo, LD, Seppänen, MRJ, Weil, R, Seminario, G, Gomez-Tello, H, Wouters, C, Mesdaghi, M, Shahrooei, M, Bossuyt, X, Sag, E, Topaloglu, R, Ozen, S, Leavis, HL, van Eijk, MMJ, Bezrodnik, L, Galicia, LB, Hovnanian, A, Nassif, A, Bader-Meunier, B, Neven, B, Meyts, I, Schrijvers, R, Puel, A, Bustamante, J, Aksentijevich, I, Kastner, DL, Torres, VJ, Humblet-Baron, S, Liston, A, Abel, L, Boisson, B & Casanova, JL 2022, 'Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin', Science, vol. 376, no. 6599, eabm6380. https://doi.org/10.1126/science.abm6380

TY - JOUR

T1 - Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin

AU - Spaan, András N.

AU - Neehus, Anna Lena

AU - Laplantine, Emmanuel

AU - Staels, Frederik

AU - Ogishi, Masato

AU - Seeleuthner, Yoann

AU - Rapaport, Franck

AU - Lacey, Keenan A.

AU - Van Nieuwenhove, Erika

AU - Chrabieh, Maya

AU - Hum, David

AU - Migaud, Mélanie

AU - Izmiryan, Araksya

AU - Lorenzo, Lazaro

AU - Kochetkov, Tatiana

AU - Heesterbeek, Dani A.C.

AU - Bardoel, Bart W.

AU - DuMont, Ashley L.

AU - Dobbs, Kerry

AU - Chardonnet, Solenne

AU - Heissel, Søren

AU - Baslan, Timour

AU - Zhang, Peng

AU - Yang, Rui

AU - Bogunovic, Dusan

AU - Wunderink, Herman F.

AU - Haas, Pieter Jan A.

AU - Molina, Henrik

AU - Van Buggenhout, Griet

AU - Lyonnet, Stanislas

AU - Notarangelo, Luigi D.

AU - Seppänen, Mikko R.J.

AU - Weil, Robert

AU - Seminario, Gisela

AU - Gomez-Tello, Héctor

AU - Wouters, Carine

AU - Mesdaghi, Mehrnaz

AU - Shahrooei, Mohammad

AU - Bossuyt, Xavier

AU - Sag, Erdal

AU - Topaloglu, Rezan

AU - Ozen, Seza

AU - Leavis, Helen L.

AU - van Eijk, Maarten M.J.

AU - Bezrodnik, Liliana

AU - Galicia, Lizbeth Blancas

AU - Hovnanian, Alain

AU - Nassif, Aude

AU - Bader-Meunier, Brigitte

AU - Neven, Bénédicte

AU - Meyts, Isabelle

AU - Schrijvers, Rik

AU - Puel, Anne

AU - Bustamante, Jacinta

AU - Aksentijevich, Ivona

AU - Kastner, Daniel L.

AU - Torres, Victor J.

AU - Humblet-Baron, Stéphanie

AU - Liston, Adrian

AU - Abel, Laurent

AU - Boisson, Bertrand

AU - Casanova, Jean Laurent

N1 - Funding Information: This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (UL1TR001866 to The Rockefeller University), the Sackler Center for Biomedicine and Nutrition at the Center for Clinical and Translational Science at The Rockefeller University and the Shapiro-Silverberg Fund for the Advancement of Translational Research (to A.N.S.), NIH P01AI061093 (to J.-L.C.), the Square Foundation, the French National Research Agency (ANR-10-IAHU-01, ANR-21-CE17-0014-03, ANR 14-CE15-0009-01, and ANR-15-CE17-0014), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (EQU201903007798), the Howard Hughes Medical Institute, the St. Giles Foundation, The Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), the Paris Cité University, the Laura and Isaac Perlmutter Cancer Center and the National Institutes of Health/National Cancer Institute (P30CA016087 to NYU Langone’s Rodent Genetic Engineering Laboratory), the Bettencourt Schueller Foundation and the International PhD program of the Imagine Institute (to A.-L.N.), the David Rockefeller Graduate Program (to M.O.), the New York Hideyo Noguchi Memorial Society (to M.O.), the Funai Foundation for Information Technology (to M.O.), the Honjo International Scholarship Foundation (to M.O.), the Cystic Fibrosis Foundation Postdoctoral Research Fellowship award (LACEY19FO to K.A.L.), the William C. and Joyce C. O’Neil Charitable Trust (to T.B.), the Memorial Sloan Kettering Single Cell Sequencing Initiative (to T.B.), the Hospital Research Funds at the Pediatric Research Center at the Helsinki University Hospital (to M.R.J.S.), and the Foundation for Pediatric Research of Finland (to M.R.J.S.). C.W. serves as a member of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (739543). The work was supported in part by the ERC Start grant IMMUNO (ERC-2010-StG_20091118 to A.L.), the VIB Grand Challenges (to A.L., S.H.-B., and R.S.), the KU Leuven BOFZAP start-up grant (to S.H.-B.), National Fund for Scientific Research senior clinical investigator fellowships (1805518N to R.S. and G0B5120N to I.M.), National Fund for Scientific Research grants (G0E8420N and G0C8517N to I.M.), a KU Leuven C1 grant (to I.M.), and the ERC Start grant MORE2ADA2 (ERC-2020-StG_948959 to I.M.). I.M. is a member of ERN-RITA. D.B. is supported by the NIH (R01 AI148963) and a founder of Lab11 Therapeutics Inc. The S. aureus work in the Torres laboratory is funded by the NIH (R01 AI099394, R01 AI105129, R01 AI121244, R01 AI137336, and R01 AI140754 to V.J.T.). V.J.T. is a Burroughs Wellcome Fund Investigator in the pathogenesis of infectious diseases. A.N.S. was supported in part by the European Union’s Horizon 2020 Research and Innovation Program (Marie Skłodowska-Curie grant 789645), the Dutch Research Council Talent Program (NWO Rubicon grant 019.171LW.015, partially nonstipendiary), and the European Molecular Biology Organization (EMBO Long-Term Fellowship grant ALTF 84-2017, nonstipendiary). Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.

PY - 2022/6/17

Y1 - 2022/6/17

N2 - 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 kB 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 a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.

AB - 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 kB 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 a-toxin. Naturally elicited antibodies against a-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to a-toxin in nonleukocytic cells.

KW - Bacterial Toxins/immunology

KW - Cri-du-Chat Syndrome/genetics

KW - Endopeptidases/genetics

KW - Haploinsufficiency/genetics

KW - Hemolysin Proteins/immunology

KW - Host-Pathogen Interactions/genetics

KW - Humans

KW - Immunity, Cellular/genetics

KW - Necrosis

KW - Staphylococcal Infections/genetics

KW - Staphylococcus aureus

UR - http://www.scopus.com/inward/record.url?scp=85132456095&partnerID=8YFLogxK

U2 - 10.1126/science.abm6380

DO - 10.1126/science.abm6380

M3 - Article

C2 - 35587511

AN - SCOPUS:85132456095

SN - 0036-8075

VL - 376

JO - Science

JF - Science

IS - 6599

M1 - eabm6380

ER -

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal a-toxin

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