Viperin restricts chikungunya virus replication and pathology.

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Chikungunya virus (CHIKV) is a reemergent mosquito-borne alphavirus causing significant arthralgia.
• The innate immune mechanisms controlling CHIKV replication are not fully understood.
• Type I interferons (IFNs) are key antiviral mediators, but their specific role in CHIKV control requires elucidation.

Purpose of the Study:

• To investigate the molecular mechanisms of the innate immune response controlling CHIKV replication.
• To identify host factors, particularly interferon-stimulated genes (ISGs), involved in limiting CHIKV infection.
• To elucidate the antiviral functions and mechanisms of RSAD2 (viperin) against CHIKV.

Main Methods:

• Longitudinal transcriptional analysis of peripheral blood mononuclear cells (PBMCs) from CHIKV-infected patients.
• Investigated the induction and cellular localization of viperin in monocytes.
• Assessed the anti-CHIKV activity of viperin through functional studies, including domain analysis.
• Utilized Rsad2-deficient mice to evaluate the in vivo role of viperin in CHIKV infection and pathogenesis.

Main Results:

• Type I IFNs control CHIKV infection primarily through the induction of RSAD2, which encodes viperin.
• Viperin expression was significantly upregulated in monocytes, the primary CHIKV target cells in blood.
• Anti-CHIKV activity of viperin was dependent on its endoplasmic reticulum (ER) localization and a specific N-terminal domain.
• Mice lacking Rsad2 exhibited increased viremia and exacerbated joint inflammation compared to wild-type controls.

Conclusions:

• Viperin is a critical antiviral host protein that effectively controls CHIKV replication.
• The study provides a preclinical foundation for developing therapeutic strategies against CHIKV and related alphaviruses.
• Understanding viperin's role offers insights into host-pathogen interactions and innate immunity against arboviruses.