Viperin restricts chikungunya virus replication and pathology

• Published in: The Journal of clinical investigation Vol. 122; no. 12; pp. 4447 - 4460
• Main Authors: Teng, Terk-Shin, Foo, Suan-Sin, Simamarta, Diane, Lum, Fok-Moon, Teo, Teck-Hui, Lulla, Aleksei, Yeo, Nicholas K.W., Koh, Esther G.L., Chow, Angela, Leo, Yee-Sin, Merits, Andres, Chin, Keh-Chuang, Ng, Lisa F.P.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.12.2012
• Subjects: Alphavirus Infections - immunology; Alphavirus Infections - pathology; Alphavirus Infections - virology; Animals; Arbovirus; Biomedical research; Case-Control Studies; Cellular proteins; Chikungunya virus; Chikungunya virus - immunology; Chikungunya virus - physiology; Clinical pathology; Cluster Analysis; Dengue fever; Disease; Endoplasmic Reticulum - metabolism; Epidemics; Female; Foot - pathology; Foot - virology; Gene Expression Regulation - immunology; Genes; Genetic aspects; HEK293 Cells; Host-Pathogen Interactions; Humans; Illnesses; Immunity, Innate - genetics; Infections; Mice; Mice, Inbred C57BL; Monocytes - metabolism; Monocytes - virology; Pathogens; Properties; Protein Structure, Secondary; Protein Structure, Tertiary; Protein Transport; Proteins - genetics; Proteins - metabolism; Proteins - physiology; Statistics, Nonparametric; Transcriptome; Virus Replication; Viruses; West Nile virus; Singapore; Southeast Asia; Africa
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI63120

Chikungunya virus (CHIKV) is a mosquito-borne arthralgia arbovirus that is reemergent in sub-Saharan Africa and Southeast Asia. CHIKV infection has been shown to be self-limiting, but the molecular mechanisms of the innate immune response that control CHIKV replication remain undefined. Here, longitudinal transcriptional analyses of PBMCs from a cohort of CHIKV-infected patients revealed that type I IFNs controlled CHIKV infection via RSAD2 (which encodes viperin), an enigmatic multifunctional IFN-stimulated gene (ISG). Viperin was highly induced in monocytes, the major target cell of CHIKV in blood. Anti-CHIKV functions of viperin were dependent on its localization in the ER, and the N-terminal amphipathic α-helical domain was crucial for its antiviral activity in controlling CHIKV replication. Furthermore, mice lacking Rsad2 had higher viremia and severe joint inflammation compared with wild-type mice. Our data demonstrate that viperin is a critical antiviral host protein that controls CHIKV infection and provide a preclinical basis for the design of effective control strategies against CHIKV and other reemerging arthrogenic alphaviruses.