RIG-I activation primes and trains innate antiviral immune memory

Abstract

Adaptive processes of the innate immune system, known as trained immunity (TI), are critical to human health and disease, yet they have not been systematically investigated downstream of antiviral sensing. Here, we elucidate the potential of the antiviral cytosolic RNA receptor retinoic acid-inducible gene I (RIG-I) to train, prime and tolerize the innate immune system. Using a specific RIG-I agonist, we observed that repetitive stimulation enhanced interferon-stimulated gene (ISG) and pro-inflammatory cytokine induction in human primary monocytes, epithelial cells and fibroblasts and afforded non-specific antiviral protection. RNA sequencing revealed broad, cell type-specific transcriptional changes, indicative of priming of ISGs and training of the NFκB pathway, without measurable tolerization, while ATAC sequencing in monocytes demonstrated chromatin remodeling and enhanced accessibility of key transcription factor-binding motifs such as STAT1. Moreover, while STAT1 signaling was critically required, it was not sufficient to recapitulate RIG-I induced TI. Altogether, our data demonstrate that RIG-I-mediated TI promotes an immunologically alert state with important implications for host defense and the application of RIG-I ligands in anti-infective and anti-tumoral therapies.

Primary nasal viral infection rewires the tissue-scale memory response

“…This difference could reflect several non-exclusive mechanisms during recall, including an overall reduction or shortening in IFN production or signaling, lower viral load, or a potential tolerized basal cell state. Airway basal cells can develop transcriptional memory in vitro (Adamson et al, 2022), but whether primary infection can confer durable memory to viral immunity, as has been seen for allergic inflammation (Ordovas-Montanes et al, 2018), requires further investigation.…”

“…Airway basal cells can develop transcriptional memory in vitro (Adamson et al, 2022), but whether primary infection can confer durable memory to viral immunity, as has been seen for allergic inflammation (Ordovas-Montanes et al, 2018), requires further investigation.…”