Retinoids inhibit measles virus through a type I IFN-dependent bystander effect.
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 (EC(50) of ATRA: 3.17 x 10(-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-muM 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
Claire
C
Department of Infectious Diseases, McGill University Health Center Research Institute, McGill University, Montreal, Quebec, Canada.
Colombo
Myrian
M
Mann
Koren K
KK
Miller
Wilson H
WH
Ward
Brian J
BJ
D024201:Bystander Effect / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology*; D008457:Measles / Q000178:diet therapy / Q000517:prevention & control; D008459:Measles virus / Q000187:drug effects*; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D014801:Vitamin A / Q000494:pharmacology
D007370:Interferon Type I; D012176:Retinoids; D014801:Vitamin A; D014212:Tretinoin