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 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. Viruses exert their pathogenicity by targeting various cellular components in infected cells. 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. 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. We also ascertained the contribution of cGAS to the in vivo pathogenicity of MeV. 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. In addition, an increased amount of mitochondrial DNA (mtDNA) in the cytosol was detected during progression of infection. 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.
Interestingly, gene ontology analysis indicated that genes encoding mitochondrial proteins are enriched among the list of downregulated genes. 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. 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.
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