# Human ISG15 and USP18 Deficiencies Underlying Type I Interferonopathies

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $423,750

## Abstract

Project Summary
 Type I Interferons (IFNs) are cytokines with well-defined anti-viral activities. While beneficial effects of
IFNs are well documented, it has become clear that IFNs also have profound detrimental effects to human
health. Disorders where dysregulated IFNs cause pathology are collectively termed type I Interferonopathies.
Mendelian type I Interferonopathy disorders like Aicardi–Goutières syndrome (AGS) and
spondyloenchondromatosis (SPENCD) showcase how constitutive upregulation of IFN activity can lead to
neurologic and autoimmune disease pathology.
 We have recently identified eleven children presenting with Mendelian type I Interferonopathy.
Genetically, we discovered six children with complete ISG15 deficiency and five children with complete USP18
deficiency. These deficiencies are the first genetic defects affecting the negative regulation of the IFN
response. ISG15 and USP18 deficient individuals present with elevated IFN stimulated genes in their blood
cells, increased resistance to viral infections, but also with neurologic and autoimmune manifestations, similar
to AGS and SPENCD. This proposal is built around the hypothesis that ISG15 and USP18 are the essential
factors controlling responsiveness to and duration of type I IFN responses.  To address this hypothesis we
propose to study these eleven rare patients in vitro, ex vivo, and in vivo at the molecular, immunological, and
clinical levels to determine the functional significance of these genes in regulating IFN pathway and resistance
to viral infections in humans.
 Deeper understanding of molecular regulation of IFN will allow us to better understand the
pathophysiology behind these deficiencies and will lay the ground for development of medicines aiding
management of persistent inflammatory disorders and/or increased anti-viral responses.

## Key facts

- **NIH application ID:** 10158443
- **Project number:** 5R01AI127372-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Dusan Bogunovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2017-06-09 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158443

## Citation

> US National Institutes of Health, RePORTER application 10158443, Human ISG15 and USP18 Deficiencies Underlying Type I Interferonopathies (5R01AI127372-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10158443. Licensed CC0.

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