Retinoic acid-inducible gene I-like receptors (RLRs) (RLRs)

Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), primarily RIG-I (DDX58) and MDA5 (IFIH1), are essential cytosolic pattern-recognition receptors (PRRs) that detect viral RNA (UniProt: O95786, Q9BYX4). In the context of the oncolytic Maraba virus vaccine MG1-hDCT, these receptors sense viral replication intermediates, such as 5-triphosphorylated RNA and double-stranded RNA (Pol et al., 2014). This sensing triggers a signaling cascade via the mitochondrial antiviral-signaling protein (MAVS), leading to the activation of IRF3 and NF-kB and the subsequent production of Type I interferons (IFNs) and pro-inflammatory cytokines (Kato et al., 2006). While this innate immune activation is essential for the booster effect of the MG1-hDCT vaccine—facilitating the recruitment and activation of T cells against the human dopachrome tautomerase (hDCT) antigen—it can also limit the direct oncolytic potential of the virus by inducing an antiviral state (Bourgeois-Daigneault et al., 2018). Consequently, RLRs are critical targets for modulation to balance the trade-off between viral-mediated tumor destruction and the induction of systemic anti-tumor immunity.

Other names

RIG-I-like receptorsCytoplasmic RNA sensorsDDX58 and IFIH1Pattern recognition receptors sensing viral RNA

RLRs recognize specific molecular patterns in viral RNA, such as 5-triphosphate ends (RIG-I) or long dsRNA (MDA5). Upon binding, they undergo ATP-dependent conformational changes and oligomerize, allowing their N-terminal CARD domains to interact with the CARD domain of the adapter protein MAVS on the outer mitochondrial membrane. This initiates a signaling complex that activates TBK1/IKK-epsilon and IKK-alpha/beta kinases, which in turn phosphorylate IRF3/7 and NF-kappaB, leading to the transcriptional induction of Type I and III interferons and other pro-inflammatory cytokines.