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Human intracellular ISG15 prevents interferon-?/? over-amplification and auto-inflammation.

ABSTRACT: Intracellular ISG15 is an interferon (IFN)-?/?-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-?/?-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-?-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-?/? immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi-Goutières syndrome and spondyloenchondrodysplasia. We further show that an absence of intracellular ISG15 in the patients' cells prevents the accumulation of USP18, a potent negative regulator of IFN-?/? signalling, resulting in the enhancement and amplification of IFN-?/? responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-?/? immunity. In humans, intracellular ISG15 is IFN-?/?-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-?/? and prevention of IFN-?/?-dependent autoinflammation.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4303590 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.

Zhang Xianqin X Bogunovic Dusan D Payelle-Brogard Béatrice B Francois-Newton Véronique V Speer Scott D SD Yuan Chao C Volpi Stefano S Li Zhi Z Sanal Ozden O Mansouri Davood D Tezcan Ilhan I Rice Gillian I GI Chen Chunyuan C Mansouri Nahal N Mahdaviani Seyed Alireza SA Itan Yuval Y Boisson Bertrand B Okada Satoshi S Zeng Lu L Wang Xing X Jiang Hui H Liu Wenqiang W Han Tiantian T Liu Delin D Ma Tao T Wang Bo B Liu Mugen M Liu Jing-Yu JY Wang Qing K QK Yalnizoglu Dilek D Radoshevich Lilliana L Uzé Gilles G Gros Philippe P Rozenberg Flore F Zhang Shen-Ying SY Jouanguy Emmanuelle E Bustamante Jacinta J García-Sastre Adolfo A Abel Laurent L Lebon Pierre P Notarangelo Luigi D LD Crow Yanick J YJ Boisson-Dupuis Stéphanie S Casanova Jean-Laurent JL Pellegrini Sandra S

Nature 20141012 7532

Intracellular ISG15 is an interferon (IFN)-α/β-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-α/β-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-γ-inducing molecule. We ...[more]

PMID: 25307056

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Project description:Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-? (IFN-? knockout [IFN-?-KO] mice or mice treated with an IFN-?-blocking antibody) or IFN-? (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-?-blocking antibody). Mice lacking either IFN-? or IFN-? developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-? sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-?-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-? had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-?-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-? limiting early viral replication and dissemination and IFN-? modulating neutrophil-mediated inflammation.IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-? and IFN-? both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-? limits CHIKV replication and dissemination, whereas IFN-? protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.

Dataset Information

Human intracellular ISG15 prevents interferon-?/? over-amplification and auto-inflammation.

Publications

Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation.

Similar Datasets

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