Dr. Silverman has investigated molecular pathways of antiviral innate immunity for the past 34 years. His studies are mainly focused on the 2’,5’-oligoadenylate (2-5A) synthetase (OAS)/RNase L system, a classical interferon-regulated, innate immune pathway that rapidly responds to PAMPs to produce a broadly active antiviral response. In prior studies, his lab purified and cloned RNase L, generated RNase L-deficient mice, established antiviral and apoptotic activities of RNase L in vivo, and determined that RNase L activation induces autophagy and initiates transcriptional signaling pathways. In current studies, he is investigating control of viral pathogenesis by regulating 2-5A turnover. His goal is to continue probing fundamental events and biologic endpoints that impact on viral replication cycles and cancer biology.
Our studies probe fundamental molecular and cellular processes that impact microbial infections and cancer. We seek a better understanding of how the mammalian cell resists viral infections and how the virus antagonizes the host response to infection. Interferons (IFNs) induce a family of 2',5'-oligoadenylate (2-5A) synthetases (OAS). In response to viral double-stranded RNA, OAS produces 2-5A whose function is to activate RNase L causing degradation of viral and cellular RNA. Previously we cloned RNase L and established its antiviral activities in genetically deficient mice. We found that RNase L cleaves viral and cellular RNA to generate small RNAs that stimulate IFN synthesis through RIG-I and MDA5. We are currently studying viral and host 2',5'-phosphodiesterases that prevent activation of RNase L, thus allowing virus replication and viral pathogenesis. Our goals include elucidating fundamental events and biologic endpoints surrounding RNase L that impact on viral replication cycles and tumor biology.
Another area of research concerns the roles of innate immunity and genetics in prostate cancer. The hereditary prostate cancer 1 (HPC1) gene maps to RNase L. We are investigating the potential role of RNase L in prostate cancer by focusing on basic cellular processes regulated by RNase L including autophagy and apoptosis. We are also developing an experimental protocol for treating late-stage cancer by combining sunitinib treatments with infection by an oncolytic virus.
- Zhang, R., Jha, B.K., Ogden, K., Dong, B., Zhao, L., Elliot, R., Patton, J.T., Silverman, R.H.* and Weiss, S.R.* Homologous 2',5'-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity. Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13114-9. doi: 10.1073/pnas.1306917110. Epub 2013 Jul 22. [*Co-corresponding authors].
- Chakrabarti, A., Ghosh, P.K., Banerjee, S., Gaughan, C., and Silverman, R.H. RNase L triggers autophagy in response to viral infections. J. Virol. 86: 11311-21, 2012.
- Malathi, K., Dong, B., Gale, M., and Silverman, R.H. Small Self RNA Generated by RNase L Amplifies Antiviral Innate Immunity. Nature, 448: 816-819, 2007.
- Der, S., Zhou, A., Williams, B.R.G., and Silverman, R.H.Identification of Genes Differentially Regulated by IFN-α β or γ or Using Oligonucleotide Arrays. Proc. Natl. Acad. Sci. U.S.A 95,15623-15628, 1998.
- Zhou, A., Hassel, B.A., and Silverman, R.H. Expression cloning of 2-5A-dependent RNase-a uniquely regulated mediator of interferon action. Cell. 1993 Mar 12;72(5):753-65.