Work from many laboratories has established that DNA sensors ? both membrane-localized Toll-like receptors (e.g. TLR9) and intracellular DNA sensors (e.g. cGAS and IFI16) ? sense herpesviral infection. In striking contrast, our knowledge about the relevance of cytoplasmic RNA sensors of the RIG-I-like receptor (RLR) family in the detection of herpesviruses remains elusive. Furthermore, the physiological RNA molecules that are recognized by RIG-I and the related sensor MDA5 during herpesvirus infection are currently unknown. The proposed study builds on a recent discovery by the Gack laboratory that RIG-I and the intracellular DNA sensors cGAS and IFI16 sense herpes simplex virus 1 (HSV-1) infection in a temporally distinct manner. Using next-generation RNA sequencing (RNA-seq), we identified that a subset of cellular non-coding RNAs, rather than viral RNAs, are bound to and activate RIG-I during HSV-1 infection. Molecular and cell biological studies in HSV-1-infected human cells revealed that viral perturbation of the natural life cycle of these host-derived RNAs allows their recognition by the sensor RIG-I, thereby stimulating the innate immune response. Using a coordinated series of molecular, biochemical and cell biological approaches combined with RNA-seq technology in HSV-1-infected cells, we will identify and characterize in precise detail the physiological RNA ligands recognized by RIG-I and MDA5 during HSV-1 infection (Aim 1). Furthermore, we will define the molecular details of how viral perturbation of the life cycle of immunostimulatory RNAs triggers an RLR-mediated immune response (Aim 2). Our studies will provide a molecular understanding of RLR-mediated innate sensing of herpesviral infection, which may provide the foundation for new therapeutic approaches or help design better vaccines.
Innate immune sensing and signaling are important first steps of the immune system to initiate an antiviral response. This study will provide new molecular insight into the mechanisms by which human cells recognize herpesvirus infection, which may catalyze the design of antiviral therapeutics or improved viral vaccines.
| van Gent, Michiel; Sparrer, Konstantin M J; Gack, Michaela U (2018) TRIM Proteins and Their Roles in Antiviral Host Defenses. Annu Rev Virol 5:385-405 |
| Chiang, Jessica J; Sparrer, Konstantin M J; van Gent, Michiel et al. (2018) Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity. Nat Immunol 19:53-62 |
