Abstract
Zika virus (ZIKV)3 is an enveloped, single-stranded, positive-sense RNA virus of the Flaviviridae family that has emerged as a public health threat because of its global transmission and link to microcephaly. Currently there is no vaccine for this virus. Conversion of cholesterol to 25-hydroxycholesterol by cholesterol 25-hydroxylase (CH25H) has been shown to have broad antiviral properties. However, the molecular basis of induction of CH25H in humans is not known. Elucidation of signaling and transcriptional events for induction of CH25H expression is critical for designing therapeutic antiviral agents. In this study, we show that CH25H is induced by ZIKV infection or Toll-like receptor stimulation. Interestingly, CH25H is induced by pro-inflammatory cytokines, including IL-1β, tumor necrosis factor α, and IL-6, and this induction depends on the STAT1 transcription factor. Additionally, we observed that cAMP-dependent transcription factor (ATF3) weakly binds to the CH25H promoter, suggesting cooperation with STAT1. However, ZIKV-induced CH25H was independent of type I interferon. These findings provide important information for understanding how the Zika virus induces innate inflammatory responses and promotes the expression of anti-viral CH25H protein.
Highlights
Zika virus (ZIKV)3 is an enveloped, single-stranded, positive-sense RNA virus of the Flaviviridae family that has emerged as a public health threat because of its global transmission and link to microcephaly
Given that ZIKV is known to trigger pattern recognition receptors, in particular TLRs [22], which, in turn, cause downstream gene induction, we examined the role of specific Toll-like receptors in inducing cholesterol 25-hydroxylase (CH25H) expression
CH25H levels in THP-1 macrophages were elevated by pro-inflammatory cytokine treatment. These results suggest that inflammatory cytokines such as IL-1, TNF␣, and IL-6 are involved in CH25H expression in human macrophages
Summary
Zika virus (ZIKV)3 is an enveloped, single-stranded, positive-sense RNA virus of the Flaviviridae family that has emerged as a public health threat because of its global transmission and link to microcephaly. Role of inflammatory cytokines in CH25H induction and E, THP-1 macrophages and microglial cells were stimulated with a control (medium only) and a panel of TLR agonists (TLR1–TLR9) for 3 h, and CH25H mRNA expression was measured by qPCR. ZIKV infection of these cell lines, like primary macrophages, significantly induced CH25H expression (Fig. 1, B and C).
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