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- Title
Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase.
- Authors
Sato, Hiroki; Hoshi, Miho; Ikeda, Fusako; Fujiyuki, Tomoko; Yoneda, Misako; Kai, Chieko
- 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. Author summary: Viruses exert their pathogenicity by targeting various cellular components in infected cells. In response, host cells have evolved strategies to sense intracellular pathogen-associated molecules, such as nucleic acids derived from infected virus, and trigger subsequent antiviral responses to counteract infection. Measles virus (MeV), the causative agent of human measles, is the most highly contagious virus, killing 300 children per day worldwide; thus MeV has been targeted for eradication by the World Health Organization. In the present study, we found that MeV causes downregulation of mitochondrial biogenesis accompanied with aberrant hyperfusion of mitochondria in the infected cells. Furthermore, we show that cytoplasmic release of mitochondrial DNA activates DNA sensor molecule, cGAS, in addition to the innate immune response induced by the viral component. Importantly, this phenomenon was also observed for viruses, both RNA and DNA, which target mitochondrial biogenesis. Our study provides new insights into the mitochondrial stress by virus infection and an important host defense system to suppress viral propagation.
- Subjects
WORLD Health Organization; MITOCHONDRIA; MITOCHONDRIAL DNA; CELL anatomy; MEASLES virus; DNA viruses; DOWNREGULATION; VIRUS diseases
- Publication
PLoS Pathogens, 2021, Vol 17, Issue 10, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1009841