Abstract
Interferons (IFNs) are the key components of innate immunity and are crucial for host defense against viral infections. Here, we report a novel role of interleukin-17A (IL-17A) in inhibiting IFN-α2 expression thus promoting chikungunya virus (CHIKV) infection. CHIKV infected IL-17A deficient (Il17a−/−) mice expressed a higher level of IFN-α2 and developed diminished viremia and milder footpad swelling in comparison to wild-type (WT) control mice, which was also recapitulated in IL-17A receptor-deficient (Il17ra−/−) mice. Interestingly, IL-17A selectively blocked IFN-α2 production during CHIKV, but not West Nile virus (WNV) or Zika virus (ZIKV), infections. Recombinant IL-17A treatment inhibited CHIKV-induced IFN-α2 expression and enhanced CHIKV replication in both human and mouse cells. We further found that IL-17A inhibited IFN-α2 production by modulating the expression of Interferon Regulatory Factor-5 (IRF-5), IRF-7, IFN-stimulated gene 49 (ISG-49), and Mx1 expression during CHIKV infection. Neutralization of IL-17A in vitro leads to the increase of the expression of these antiviral molecules and decrease of CHIKV replication. Collectively, these results suggest a novel function of IL-17A in inhibiting IFN-α2–mediated antiviral responses during CHIKV infection, which may have broad implications in viral infections and other inflammatory diseases.
Highlights
Chikungunya virus (CHIKV) is a reemerging mosquito-transmitted alphavirus of the Togaviridae family that can cause crippling musculoskeletal inflammatory disease in humans that is characterized by fever, polyarthralgia, myalgia, rash, and headache
ELISA results showed significant increases of IL-17A at protein levels in the NIH3T3 cell culture (Figure 1E) and the plasma samples on days 1 (D1) p.i. (Figure 1F). These results demonstrate that chikungunya virus (CHIKV) infection induces the expression of IL-17A in physiologically relevant human and mouse cells and mice
We infected NIH3T3 cells with CHIKV in the presence of recombinant mouse IL-17A (rIL-17A) for quantitative PCR (QPCR) analysis, and the results showed that the expression of Irf-3, Irf-5, and Irf-7 was inhibited at the transcriptional levels (Figures 5A–C)
Summary
Chikungunya virus (CHIKV) is a reemerging mosquito-transmitted alphavirus of the Togaviridae family that can cause crippling musculoskeletal inflammatory disease in humans that is characterized by fever, polyarthralgia, myalgia, rash, and headache. CHIKV, first isolated in 1953 in Tanzania, was endemic in the tropic regions of Africa and the Indian Ocean [1]. Due to the increasing human travel and the rapid spread of the mosquito vectors to cooler climates, CHIKV has dramatically expanded its territory and is currently circulating in over 60 countries, including Africa, Asia, Europe, and the Americas [2]. Since its introduction to the western hemisphere in 2013, CHIKV has caused an explosive epidemic in the Americas with over two million febrile cases with debilitating polyarthralgia in about 50 countries [3]. There are no specific treatments or vaccines currently available, and the pathogenesis of CHIKV is largely unknown.
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