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Science 337 (6102): 1684-1688

Copyright © 2012 by the American Association for the Advancement of Science

Mycobacterial Disease and Impaired IFN-{gamma} Immunity in Humans with Inherited ISG15 Deficiency

Dusan Bogunovic,1 Minji Byun,1 Larissa A. Durfee,2,* Avinash Abhyankar,1,* Ozden Sanal,3,* Davood Mansouri,4,* Sandra Salem,5,* Irena Radovanovic,5 Audrey V. Grant,6 Parisa Adimi,4 Nahal Mansouri,1,4 Satoshi Okada,1 Vanessa L. Bryant,1 Xiao-Fei Kong,1 Alexandra Kreins,1 Marcela Moncada Velez,1 Bertrand Boisson,1 Soheila Khalilzadeh,4 Ugur Ozcelik,3 Ilad Alavi Darazam,4 John W. Schoggins,7 Charles M. Rice,7 Saleh Al-Muhsen,8,9 Marcel Behr,10 Guillaume Vogt,1,6 Anne Puel,6 Jacinta Bustamante,6,11,{dagger} Philippe Gros,5,{dagger} Jon M. Huibregtse,2,{dagger} Laurent Abel,1,6,{dagger} Stéphanie Boisson-Dupuis,1,6 Jean-Laurent Casanova1,6,12,{ddagger}

Abstract: ISG15 is an interferon (IFN)-α/β–inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes—granulocyte, in particular—reduced the production of IFN-{gamma} by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-{gamma}–inducing secreted molecule for optimal antimycobacterial immunity.

1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
2 Section of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
3 Immunology Division and Pediatric Chest Disease Department, Hacettepe University Children’s Hospital, 06100 Ankara, Turkey.
4 Division of Infectious Diseases and Clinical Immunology, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Teheran, Iran.
5 Department of Biochemistry, McGill University, Montreal, Canada.
6 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, U980, University Paris Descartes, Necker Medical School, 75015 Paris, France.
7 Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
8 Prince Naif Center for Immunology Research, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, 11211, Saudi Arabia.
9 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia.
10 Research Institute, McGill University Health Center, Montreal, Canada.
11 Center for the Study of Primary Immunodeficiencies, Assistance Publique–Hopitaux de Paris, Necker Hospital, Paris, France.
12 Pediatric Hematology-Immunology Unit, Necker Hospital, 75015 Paris, France.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: casanova{at}

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