ISG15 Drives Immune Pathology and Respiratory Failure during Systemic Lymphocytic Choriomeningitis Virus Infection

Area of Science:

• Immunology
• Virology
• Pathology

Background:

• Interferon-stimulated gene 15 (ISG15) is crucial for antiviral immunity but can cause pathology in persistent infections.
• Understanding ISG15's dual role is key for developing therapies against viral diseases.

Purpose of the Study:

• To investigate the role of USP18 enzymatic function and ISG15 in immune pathology during persistent viral infections.
• To identify potential therapeutic targets for severe viral infections.

Main Methods:

• Utilized Usp18-deficient, USP18 enzymatic-inactive, and Isg15-deficient mouse models.
• Examined the effects of interrupting ISG15 conjugation/deconjugation enzymes (Uba7, Usp18).
• Investigated the role of myeloid cells and performed myeloid cell depletion.

Main Results:

• Lack of USP18 enzymatic function caused severe pathology, including hematological disruptions, pulmonary inflammation, vascular leakage, and death.
• Myeloid cell-specific Usp18 deficiency mimicked these pathologies and required ISG15.
• Interfering with ISG15 conjugation/deconjugation led to ISG15 accumulation, neutrophil infiltration, lung pathology, and death.

Conclusions:

• Dysregulated ISG15 production and signaling during persistent viral infections can cause lethal immune pathology.
• Targeting ISG15 signaling may be beneficial for treating severe viral infections with pulmonary manifestations.