Oral Presentation Lorne Infection and Immunity 2013

Argonautes in the mammalian antiviral defense (#6)

Kate Jeffrey 1
  1. Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

RNA interference (RNAi) is a potent sequence-specific means of gene silencing guided by double-stranded, non-coding RNA that is highly conserved. RNAi is controlled by the RNA-induced silencing complex (RISC) and is initiated by short double-stranded RNA molecules, produced by the RNase III endonuclease Dicer from endogenous or exogenous RNA templates, where they interact with the catalytic RISC component Argonaute (AGO). Plants, insects and C.elegans all use RNAi for silencing viral RNA. Indeed, deletion of AGOs or Dicer in these lower organisms demonstrated their direct role in suppressing virus replication. The key RNAi effector proteins, Dicer and AGO1-4, are functional in mammalian cells and execute RNAi as well as micro (mi)RNA responses for endogenous gene silencing. Whether mammalian cells still use RNAi/miRNA devices for antiviral defense remains a largely unanswered question of innate immunity. It is generally thought that pattern recognition receptors (PRR)s leading to the production of antiviral cytokines such as type I interferon have made RNAi mechanisms for antiviral immunity redundant.

Using AGO1, 2, 3 and 4 deficient mice we demonstrate profound but differential contributions of AGO1-4 to mammalian antiviral responses to multiple viruses, that is independent of type I interferon production. In addition, high throughput sequencing of RNA bound to AGOs in virus infected cells revealed RNA populations bound to AGOs in primary macrophages. These results will be discussed.