Abstract
Vitamin A can significantly decrease measles-associated morbidity and mortality. Vitamin A can inhibit the replication of measles virus (MeV) in vitro through an RARα- and type I interferon (IFN)-dependent mechanism. Retinoid-induced gene I (RIG-I) expression is induced by retinoids, activated by MeV RNA and is important for IFN signaling. We hypothesized that RIG-I is central to retinoid-mediated inhibition of MeV in vitro. We demonstrate that RIG-I expression is increased in cells treated with retinoids and infected with MeV. The central role of RIG-I in the retinoid-anti-MeV effect was demonstrated in the Huh-7/7.5 model; the latter cells having non-functional RIG-I. RAR-dependent retinoid signaling was required for the induction of RIG-I by retinoids and MeV. Retinoid signaling was also found to act in combination with IFN to induce high levels of RIG-I expression. RIG-I promoter activation required both retinoids and MeV, as indicated by markers of active chromatin. IRF-1 is known to be regulated by retinoids and MeV, but we found recruitment of IRF-1 to the RIG-I promoter by retinoids alone. Using luciferase expression constructs, we further demonstrated that the IRF-1 response element of RIG-I was required for RIG-I activation by retinoids or IFN. These results reveal that retinoid treatment and MeV infection induces significant RIG-I. RIG-I is required for the retinoid-MeV antiviral response. The induction is dependent on IFN, retinoids and IRF-1.
Highlights
In 2007 measles was responsible for 197 000 deaths, the lowest rate ever reported [1]
measles virus (MeV) infection alone resulted in a small increase in Retinoid-induced gene I (RIG-I) mRNA, while all trans retinoic acid (ATRA) treatment alone had no discernible effect on RIG-I expression in this cell line
Retinol (Vitamin A) is known to have significant clinical benefit in natural MeV infection, and we have shown that retinoids can have powerful anti-MeV effects in vitro [2,3,8]
Summary
In 2007 measles was responsible for 197 000 deaths, the lowest rate ever reported [1]. Morbidity and mortality due to measles can be significantly reduced with two doses of retinol (200,000 IU; water-based formulation) [2,3,4]. Since the mid1990s, the WHO and UNICEF have recommended vitamin A treatment for acute measles in regions of the developing world with high mortality rates [5]. The active retinol metabolite, all trans retinoic acid (ATRA) is responsible for mediating many of the important functions of retinoids. ATRA is the natural ligand for the retinoic acid receptors (RARs), which form heterodimers with the retinoid X receptors (RXRs) within the nucleus [7]. RAR-RXR heterodimers bind to retinoid acid response elements (RAREs) on the promoters of target genes to activate transcription of these genes when bound by ligand [4]
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