Innate sensing of picornavirus infection involves cGAS-STING-mediated antiviral responses triggered by mitochondrial DNA release

PLoS Pathog. 2023 Feb 6;19(2):e1011132. doi: 10.1371/journal.ppat.1011132. eCollection 2023 Feb.

Abstract

Cyclic GMP-AMP synthase (cGAS) plays a key role in the innate immune responses to both DNA and RNA virus infection. Here, we found that enterovirus 71 (EV-A71), Seneca Valley virus (SVV), and foot-and-mouth disease virus (FMDV) infection triggered mitochondria damage and mitochondrial DNA (mtDNA) release in vitro and vivo. These responses were mediated by picornavirus 2B proteins which induced mtDNA release during viral replication. SVV infection caused the opening of mitochondrial permeability transition pore (mPTP) and led to voltage-dependent anion channel 1 (VDAC1)- and BCL2 antagonist/killer 1 (Bak) and Bak/BCL2-associated X (Bax)-dependent mtDNA leakage into the cytoplasm, while EV-A71 and FMDV infection induced mPTP opening and resulted in VDAC1-dependent mtDNA release. The released mtDNA bound to cGAS and activated cGAS-mediated antiviral immune response. cGAS was essential for inhibiting EV-A71, SVV, and FMDV replication by regulation of IFN-β production. cGAS deficiency contributed to higher mortality of EV-A71- or FMDV-infected mice. In addition, we found that SVV 2C protein was responsible for decreasing cGAS expression through the autophagy pathway. The 9th and 153rd amino acid sites in 2C were critical for induction of cGAS degradation. Furthermore, we also show that EV-A71, CA16, and EMCV 2C antagonize the cGAS-stimulator of interferon genes (STING) pathway through interaction with STING, and highly conserved amino acids Y155 and S156 were critical for this inhibitory effect. In conclusion, these data reveal novel mechanisms of picornaviruses to block the antiviral effect mediated by the cGAS-STING signaling pathway, which will provide insights for developing antiviral strategies against picornaviruses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / metabolism
  • DNA, Mitochondrial / genetics
  • Foot-and-Mouth Disease Virus* / genetics
  • Immunity, Innate
  • Interferon-beta / metabolism
  • Mice
  • Mitochondria / metabolism
  • Nucleotidyltransferases / metabolism
  • Picornaviridae
  • Picornaviridae Infections* / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism

Substances

  • Antiviral Agents
  • DNA, Mitochondrial
  • Interferon-beta
  • Nucleotidyltransferases
  • Proto-Oncogene Proteins c-bcl-2
  • Sting1 protein, mouse

Supplementary concepts

  • Senecavirus A

Grants and funding

This work was supported by the National Natural Sciences Foundation of China (32102638 to HL, 32102639 to FY, and 31972688 to HZ), the grants from the National Key R&D Program of China (2021YFD1800300 to XL), the Key Technologies R&D Program of Gansu Province (21ZD3NA001 to HZ, 20ZD7NA006 to HZ, and 19ZDNA001 to HZ), the Open Competition Program of Top Ten Critical Priorities of Agricultural Science and Technology Innovation for the 14th Five-Year Plan of Guangdong Province (2022SDZG02 to HZ), and the Earmarked Fund for CARS-35 (to HZ) and CARS-39-13 (to HZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.