The Potential of STING Modulation as Broad-spectrum Host Antiviral Therapeutics for RNA Viruses

Abstract

The type I interferon (IFN-I) response is a crucial antiviral defense mechanism that is primarily activated by the detection of cytoplasmic DNA via the cGAS-STING pathway or cytoplasmic viral RNA via the RLR-MAVS pathway. While STING was initially recognized for its role in DNA virus immunity, emerging evidence suggests that it also plays a key role in defense against RNA viruses, by acting as a convergence point downstream of cGAS and RLR-MAVS signaling, prior to interferon gene transcription. In accordance, STING is shown to be necessary for inducing antiviral interferons and conferring resistance to RNA virus infections. However, abnormal STING signaling is suggested as the driver behind the dysregulated or delayed IFN-I responses linked to impaired viral clearance and excessive inflammation, as observed in severe cases of RNA virus diseases such as COVID-19 and dengue. This is of utmost importance as high-priority pathogens for viral outbreaks, as indicated by the WHO, are mostly RNA viruses. Despite its significance, STING has yet to be explored as a broad-spectrum host-directed strategic target (HDST). Given the increasing need for host-targeted therapeutic approaches in pandemic preparedness, STING represents a promising candidate due to its central role in antiviral immunity and IFN-I response disruption in severe viral diseases. Therefore, this article will first consider STING as a potential broad-spectrum HDST by considering, 1) how do RNA viruses on the WHO Priority Pathogen List disrupt STING signaling for immune evasion? Following, the article will explore, 2) what are current potential strategies and challenges in leveraging STING modulation as broad-spectrum host-directed therapeutics? Exploring the relevance of STING in immunity against RNA viruses and the strategic modulations within its pathway could offer novel insights into enhancing viral clearance, reducing inflammation, and improving disease outcomes across a broad spectrum of RNA viruses. This, in turn, could strengthen global health security by improving protection, preparedness, and response to emerging and re-emerging viral threats.