Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency

Dusan Bogunovic, Minji Byun, Larissa A. Durfee, Avinash Abhyankar, Ozden Sanal, Davood Mansouri, Sandra Salem, Irena Radovanovic, Audrey V. Grant, Parisa Adimi, Nahal Mansouri, Satoshi Okada, Vanessa L. Bryant, Xiao Fei Kong, Alexandra Kreins, Marcela Moncada Velez, Bertrand Boisson, Soheila Khalilzadeh, Ugur Ozcelik, Ilad Alavi DarazamJohn W. Schoggins, Charles M. Rice, Saleh Al-Muhsen, Marcel Behr, Guillaume Vogt, Anne Puel, Jacinta Bustamante, Philippe Gros, Jon M. Huibregtse, Laurent Abel, Stéphanie Boisson-Dupuis, Jean Laurent Casanova

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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-γ 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-γ - inducing secreted molecule for optimal antimycobacterial immunity.

Original languageEnglish (US)
Pages (from-to)1684-1688
Number of pages5
JournalScience
Volume337
Issue number6102
DOIs
Publication statusPublished - Sep 28 2012

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Bogunovic, D., Byun, M., Durfee, L. A., Abhyankar, A., Sanal, O., Mansouri, D., ... Casanova, J. L. (2012). Mycobacterial disease and impaired IFN-γ immunity in humans with inherited ISG15 deficiency. Science, 337(6102), 1684-1688. https://doi.org/10.1126/science.1224026