Imiquimod suppresses propagation of herpes simplex virus 1 by upregulation of cystatin a via the adenosine receptor A<inf>1</inf>pathway

• Main Authors: Yuji Kan, Tamaki Okabayashi, Shin Ichi Yokota, Soh Yamamoto, Nobuhiro Fujii, Toshiharu Yamashita
• Other Authors: Sapporo Medical University School of Medicine
• Format: Article
• Published: 2018
• Subjects: Agricultural and Biological Sciences; Immunology and Microbiology
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/13389
• Institution: Mahidol University

Imiquimod is recognized as an agonist for Toll-like receptor 7 (TLR7) in immunocompetent cells. TLR7, as well as TLR3 and TLR8, triggers the immune responses, such as the production of type I interferons (IFNs) and proinflammatory cytokines via recognition of viral nucleic acids in the infected cells. In this study, we proposed that imiquimod has an IFN-independent antiviral effect in nonimmune cells. Imiquimod, but not resiquimod, suppressed replication of human herpes simplex virus 1 (HSV-1) in FL cells. We analyzed alternation of gene expression by treatment with imiquimod using microarray analysis. Neither type I IFNs, nor TLRs, nor IFN-inducible antiviral genes were induced in imiquimod-treated FL cells. Cystatin A, a host cysteine protease inhibitor, was strongly upregulated by imiquimod and took a major part in the anti-HSV-1 activity deduced by the suppression experiment using its small interfering RNA. Upregulation of cystatin A was suggested to be mediated by antagonizing adenosine receptor A1 and activating the protein kinase A pathway. Imiquimod, but not resiquimod, was shown to interact with adenosine receptor A1. Imiquimod-induced anti-HSV-1 activity was observed in other cells, such as HeLa, SiHa, and CaSki cells, in a manner consistent with the cystatin A induction by imiquimod. These results indicated that imiquimod acted as an antagonist for adenosine receptor A1 and induced a host antiviral protein, cystatin A. The process occurred independently of TLR7 and type I IFNs. © 2012, American Society for Microbiology.