Retinoids inhibit measles virus through a type I IFN-dependent bystander effect

• Published in: The FASEB journal Vol. 23; no. 9; pp. 3203 - 3212
• Main Authors: Trottier, Claire, Colombo, Myrian, Mann, Koren K, Miller, Wilson H. Jr, Ward, Brian J
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01-09-2009
• Subjects: all-trans retinoic acid; Bystander Effect - drug effects; Cell Line; Humans; Immunity, Innate; Interferon Type I - immunology; Measles - diet therapy; Measles - prevention & control; Measles virus - drug effects; paramyxovirus; Retinoids - pharmacology; Signal Transduction - immunology; Tretinoin - pharmacology; Virus Replication - drug effects; Vitamin A; Vitamin A - pharmacology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.09-129288

Measles-associated mortality can be decreased in response to treatment with vitamin A. Our goal was to understand the mechanism by which vitamin A and other retinoids reduce measles virus (MeV) replication in vitro. MeV is known to inhibit type I interferon (IFN) signaling, and retinoids are increasingly implicated in modulating innate immunity. Type I IFN blocking antibodies abrogated the inhibitory effects of all-trans retinoic acid (ATRA) on MeV replication (EC₅₀ of ATRA: 3.17x10⁻⁸ M). IFN-stimulated genes (ISGs) are up-regulated by ATRA in MeV-infected U937 cell cultures starting at 12 h and reaching a plateau at 24 h postinfection when compared to either treatment or infection alone. We found that this increased gene expression occurs in uninfected cells by using a transwell system where the uninfected cells were separated from infected cells by a membrane with 0.02-μM pores. Uninfected bystander cells from the ATRA-treated transwells did not support substantial viral replication when subsequently infected with MeV. In the absence of ATRA, the cells from the uninfected chamber did not up-regulate ISG expression and were not protected from subsequent challenge with virus. These results demonstrate that retinoids inhibit MeV replication by up-regulating elements of the innate immune response in uninfected bystander cells, making them refractory to productive infection during subsequent rounds of viral replication.--Trottier, C., Colombo, M., Mann, K. K., Miller, W. H., Jr., Ward, B. J. Retinoids inhibit measles virus through a type I IFN-dependent bystander effect.