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

Claire Trottier^*,, Myrian Colombo, Koren K. Mann, Wilson H. Miller, Jr.^,1 and Brian J. Ward^*,1

^* Department of Infectious Diseases, McGill University Health Center Research Institute; and

Segal Cancer Center, Lady Davis Institute for Medical Research, SMBD Jewish General Hospital, McGill University, Montreal, Quebec, Canada

¹ Correspondence: B.J.W., Montreal General Hospital Research Institute, L10.309, 1650 Cedar Ave., Montreal, Quebec, Canada H3G 1A4. E-mail: brian.ward{at}mcgill.ca; W.H.M., Segal Cancer Center, Lady Davis Institute of the Jewish General Hospital, 3755 Côte Ste-Catherine Rd., E-504, Montreal, Quebec, Canada H3T 1E2. E-mail: wmiller{at}ldi.jgh.mcgill.ca

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.

Key Words: Vitamin A • paramyxovirus • all-trans retinoic acid