SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology

Cell Host Microbe. 2017 Mar 8;21(3):344-355. doi: 10.1016/j.chom.2017.01.015. Epub 2017 Feb 16.

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) causes lethal disease in humans, which is characterized by exacerbated inflammatory response and extensive lung pathology. To address the relevance of small non-coding RNAs in SARS-CoV pathology, we deep sequenced RNAs from the lungs of infected mice and discovered three 18-22 nt small viral RNAs (svRNAs). The three svRNAs were derived from the nsp3 (svRNA-nsp3.1 and -nsp3.2) and N (svRNA-N) genomic regions of SARS-CoV. Biogenesis of CoV svRNAs was RNase III, cell type, and host species independent, but it was dependent on the extent of viral replication. Antagomir-mediated inhibition of svRNA-N significantly reduced in vivo lung pathology and pro-inflammatory cytokine expression. Taken together, these data indicate that svRNAs contribute to SARS-CoV pathogenesis and highlight the potential of svRNA-N antagomirs as antivirals.

Keywords: SARS-CoV; antagomirs; antiviral; coronavirus; deep sequencing; innate immune response; lung inflammatory pathology; non-coding RNAs; small viral RNAs; virus-host interaction.

MeSH terms

  • Animals
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • High-Throughput Nucleotide Sequencing
  • Lung / pathology*
  • Mice
  • RNA, Small Untranslated / genetics
  • RNA, Small Untranslated / metabolism*
  • RNA, Viral / genetics
  • RNA, Viral / metabolism*
  • Severe Acute Respiratory Syndrome / pathology*
  • Severe Acute Respiratory Syndrome / virology*
  • Severe acute respiratory syndrome-related coronavirus / pathogenicity*

Substances

  • Cytokines
  • RNA, Small Untranslated
  • RNA, Viral