Innate Immune DNA Sensing of Flaviviruses

Abstract

Flaviviruses are arthropod-borne RNA viruses that have been used extensively to study host antiviral responses. Often selected just to represent standard single-stranded positive-sense RNA viruses in early studies, the Flavivirus genus over time has taught us how truly unique it is in its remarkable ability to target not just the RNA sensory pathways but also the cytosolic DNA sensing system for its successful replication inside the host cell. This review summarizes the main developments on the unexpected antagonistic strategies utilized by different flaviviruses, with RNA genomes, against the host cyclic GAMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway in mammalian systems. On the basis of the recent advancements on this topic, we hypothesize that the mechanisms of viral sensing and innate immunity are much more fluid than what we had anticipated, and both viral and host factors will continue to be found as important factors contributing to the host innate immune system in the future.

Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

“…For instance, HBV infection leads to a decrease in cGAS and STING expression in infected hepatocytes-derived cells and infected liver, both in vitro and in vivo ( 86 ). Importantly, numerous members of the RNA virus family Flaviviridae exhibit an impressive variety of mechanisms regulating the cGAS-STING pathway [reviewed in ( 93 )], such as dengue virus (DENV) protease cofactor NS2B that triggers cGAS degradation in an autophagy-dependent manner ( 94 ) and Zika virus NS1 that prevents caspase-1 degradation, leading to cGAS cleavage and modulation of type I IFN signaling ( 95 ). At the current stage of our knowledge, no typical genomic or intermediary structures from Flaviviruses are susceptible to be detected by cGAS, raising the question of RNA virus evolution leading to the counteraction of this innate immune pathway in the absence of direct sensing ( 93 ).…”

“…Importantly, numerous members of the RNA virus family Flaviviridae exhibit an impressive variety of mechanisms regulating the cGAS-STING pathway [reviewed in ( 93 )], such as dengue virus (DENV) protease cofactor NS2B that triggers cGAS degradation in an autophagy-dependent manner ( 94 ) and Zika virus NS1 that prevents caspase-1 degradation, leading to cGAS cleavage and modulation of type I IFN signaling ( 95 ). At the current stage of our knowledge, no typical genomic or intermediary structures from Flaviviruses are susceptible to be detected by cGAS, raising the question of RNA virus evolution leading to the counteraction of this innate immune pathway in the absence of direct sensing ( 93 ). Of note, independently from cGAS, influenza A viral particles have been shown to directly interact the STING through its fusion peptide, thus stimulating IFN response ( 96 ).…”

“…Notably, viral oncogenes, such as E7 from the human papillomavirus (HPV), E1A from the adenovirus, and the simian virus 40 (SV40) large T antigen have been shown to modulate the cGAS/STING pathway ( 98 , 99 ). In the specific case of Flaviviruses, it has been proposed that leaking mitochondrial DNA coming from damaged mitochondria upon DENV infection may trigger cGAS activation in the cytoplasm of infected cells ( 93 ). A more comprehensive knowledge of cGAS ligands is still required to understand the complex interaction between cGAS and the diversity of virus infections.…”

Special Issue: “Innate Immune Sensing of Viruses and Viral Evasion”

“…These publications exemplify the fact that viruses have evolved multiple ways to dampen the host IFN response by interfering, disrupting, or evading specific host regulators, both up-and downstream of IFN induction. The diverse viral escape pathways are described in the following reviews [7,8,[10][11][12][13] and one original article on herpes-viruses [14]. A recent discovery stems from the observation that DNA sensing by the cGAS/STING pathway can be triggered by certain RNA viruses.…”

“…A recent discovery stems from the observation that DNA sensing by the cGAS/STING pathway can be triggered by certain RNA viruses. Zhu et al describe an unexpected strategy of flaviviruses to antagonize this DNA sensing pathway [ 12 ]. Im-portant players in recognizing and sensing RNA viruses are described for HDV [ 10 ] and Influenza virus [ 15 ].…”