Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase

Abstract

In general, in mammalian cells, cytosolic DNA viruses are sensed by cyclic GMP-AMP synthase (cGAS), and RNA viruses are recognized by retinoic acid-inducible gene I (RIG-I)-like receptors, triggering a series of downstream innate antiviral signaling steps in the host. We previously reported that measles virus (MeV), which possesses an RNA genome, induces rapid antiviral responses, followed by comprehensive downregulation of host gene expression in epithelial cells. Interestingly, gene ontology analysis indicated that genes encoding mitochondrial proteins are enriched among the list of downregulated genes. To evaluate mitochondrial stress after MeV infection, we first observed the mitochondrial morphology of infected cells and found that significantly elongated mitochondrial networks with a hyperfused phenotype were formed. In addition, an increased amount of mitochondrial DNA (mtDNA) in the cytosol was detected during progression of infection. Based on these results, we show that cytosolic mtDNA released from hyperfused mitochondria during MeV infection is captured by cGAS and causes consequent priming of the DNA sensing pathway in addition to canonical RNA sensing. We also ascertained the contribution of cGAS to the in vivo pathogenicity of MeV. In addition, we found that other viruses that induce downregulation of mitochondrial biogenesis as seen for MeV cause similar mitochondrial hyperfusion and cytosolic mtDNA-priming antiviral responses. These findings indicate that the mtDNA-activated cGAS pathway is critical for full innate control of certain viruses, including RNA viruses that cause mitochondrial stress.

Crosstalk between RNA viruses and DNA sensors: Role of the cGAS‐STING signalling pathway

“…[76][77][78] Similarly, researchers revealed that plasmid DNA transfection activates the cGAS-STING pathway, preparing the cells to be in an antiviral state that compromises the infectivity of coxsackievirus B3 (CVB3). 79 The cGAS-STING pathway also robustly evokes IFN response and effectively inhibits infection of several other RNA viruses, including chikungunya virus (CHIKV), 80,81 encephalomyocarditis virus (EMCV), 68,71 hepatitis C virus (HCV), 82 influenza A virus (IAV), 71,83 measles virus (MeV), 84,85 murine norovirus (MNV), 86,87 Nipah virus (NiV), 84 and Zika virus (ZIKV). 88 Surprisingly, in addition to antiviral role, STING has been discovered to be proviral in rare cases of RNA viral infections.…”

“…71 A number of studies have reported that RNA viral infection can induce mtDNA leakage, consequently prompting the activation of the cGAS-STING axis. For example, infection with CHIKV, 81 DENV, 64,65 IAV, 71 MeV, 85 and MNV 86 EMCV infection, respectively, in a mitochondrial antiviral signalling (MAVS)-dependent manner. 71 (Figure 2).…”

Control of innate immunity by the cGAS‐STING pathway

“…RNA viruses such as measles virus, which do not possess cGAS ligands, induce mtDNA-dependent cGAS activation in addition to activating RNA sensing pathways. 84 During intrinsic apoptosis, Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP) triggers the cytosolic release of mtDNA that activates cGAS and STING, which is inhibited by apoptotic caspases (caspase-9 and caspase-3/7) that are downstream of MOMP. 85,86 The mechanism by which these caspases inhibit cGAS-STING activation is likely via the cleavage of cGAS, as described later.…”

“…The perturbation of mitochondrial function either by infectious or non‐infectious stimuli leads to mitochondrial damage that releases mtDNA into the cytosol. RNA viruses such as measles virus, which do not possess cGAS ligands, induce mtDNA‐dependent cGAS activation in addition to activating RNA sensing pathways 84 . During intrinsic apoptosis, Bax/Bak‐mediated mitochondrial outer membrane permeabilization (MOMP) triggers the cytosolic release of mtDNA that activates cGAS and STING, which is inhibited by apoptotic caspases (caspase‐9 and caspase‐3/7) that are downstream of MOMP 85,86 .…”

Mitochondria: intracellular sentinels of infections

“…inflammatory signals acting on mitochondrial physiology—has been described in this axis. In epithelial cell infections with measles virus (MeV), a negative-sense single-stranded RNA (-ssRNA) virus, recent findings showed that mitochondrial biogenesis is downregulated and mitochondrial elongation can be observed [ 108 ]. In addition, the release of mtDNA into the cytosol has been detected, and activation of the cGAS/STING axis led to an antiviral response.…”