Sensing of viral lung infections by cGAS-STING

Abstract

Lower respiratory tract infections caused over 4 million deaths per year worldwide, especially in low-income countries. Viral respiratory infections often occur as rapidly spreading seasonal endemic or epidemic, and sometimes due to new respiratory viruses including corona viruses. The first level of host defense against viral infection is based on the innate immune system and intracellular killing mechanisms. The latter is activated by the release of viral DNA or RNA into the cytosol of the infected cells during the initial phase of virus replication. Viral DNA and RNA are recognized by the cyclic guanosine monophosphate (cGMP)-adenosine monophosphate (AMP) synthase (cGAS)–stimulator of interferon (IFN) genes (STING) sensing pathway, leading to the activation of type-I and -III IFN synthesis, with the aim to limit viral replication. However, the efficacy of the cGAS-STING sensing mechanism seems to vary with different viruses, and therefore, so is the efficacy of the host defense mechanism. Viral DNA can be sensed by different proteins including DNA-dependent activator of IFN regulating factor (DAI), cGAS, and toll-like receptor-9 (TLR-9). Viral RNA is recognized by retinoid acid-inducible gene 1 (RIG-1), TLR-7 and TLR-8. The question if cGAS also recognizes viral RNA remains unclear. The activation of IFN synthesis by cGAS is initiated by the recognition of purines and pyrimidines and their enzymatic conversion into cGMP and cyclic AMP (cAMP), followed by the activation of STING. In addition, it is indicated that several viruses can evade the cGAS-STING signaling and escape the host defense. This review aims to summarize the role of cGAS-STING as a host defense mechanism against viral respiratory tract infections.

SARS-CoV-2 infection activates the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in the lung: a review

“…The effect of SARS-CoV-2 infection on host defense is not yet fully understood. A transcriptomic analysis of patients who died from acute respiratory distress syndrome (ARDS) during the first outbreak of SARS-CoV showed that IFNs and IRF3 were upregulated, suggesting activation of the cGAS-STING pathway signaling [34].…”

“…This converts adenosine triphosphate (ATP) and guanosine triphosphate to form a second messenger cGAMP, which binds to STING, and induces its dimerization and translocation to perinuclear proteins. Subsequently, in late stages of COVID-19, it is suggested to activate TRAF6 and STING phosphorylates TBK1, which in turn activates NF-κB p65 leading to the synthesis of IFN-I and cytokines [31,34] (Figure 3). Therefore, dsDNA activates cGAS, which goes on to synthesize cGAMP.…”