Viperin restricts chikungunya virus replication and pathology
Terk-Shin Teng, … , Keh-Chuang Chin, Lisa F.P. Ng
Terk-Shin Teng, … , Keh-Chuang Chin, Lisa F.P. Ng
Published November 19, 2012
Citation Information: J Clin Invest. 2012;122(12):4447-4460. https://doi.org/10.1172/JCI63120.
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Research Article Virology

Viperin restricts chikungunya virus replication and pathology

Abstract

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.

Authors

Terk-Shin Teng, Suan-Sin Foo, Diane Simamarta, Fok-Moon Lum, Teck-Hui Teo, Aleksei Lulla, Nicholas K.W. Yeo, Esther G.L. Koh, Angela Chow, Yee-Sin Leo, Andres Merits, Keh-Chuang Chin, Lisa F.P. Ng

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Figure 2

Viperin is induced mainly in monocytes during human whole blood infection.

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Viperin is induced mainly in monocytes during human whole blood infectio...
(A) Whole blood was collected from healthy donors, and the total leukocyte count was determined before performing infection with HI CHIKV (control) or CHIKV (MOI 10) for 12 hours. Total PBMCs were purified, and a fraction was used for flow cytometry analysis to determine percent CHIKV Ag+ cells in the indicated PBMC subsets (see Supplemental Figure 3). Data are mean ± SD for each subset (n = 3). Horizontal dotted line represents the mean in HI CHIKV–infected controls. (B) Detection of CHIKV viral load in nonsorted and sorted PBMCs. Total RNA was extracted from each indicated cell population, and the amount of CHIKV viral load was determined by qRT-PCR using specific primers against the negative-strand nsP1 RNA. Data are mean ± SD (n = 3). Horizontal dotted line represents the mean in HI CHIKV–infected controls. (C) qRT-PCR was used to determine the expression profiles of type I IFNs and related ISGs in the sorted PBMC subsets as well as the nonsorted PBMC fractions. Data obtained were normalized to GAPDH and presented as expression relative to each cell population from controls infected with HI CHIKV. Data are mean ± SD (n = 3). *P < 0.05, 1-way ANOVA with Tukey’s post-test.