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MERS-CoV endoribonuclease and accessory proteins jointly evade host innate immunity during infection of lung and nasal epithelial cells.
Comar, Courtney E; Otter, Clayton J; Pfannenstiel, Jessica; Doerger, Ethan; Renner, David M; Tan, Li Hui; Perlman, Stanley; Cohen, Noam A; Fehr, Anthony R; Weiss, Susan R.
  • Comar CE; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104.
  • Otter CJ; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
  • Pfannenstiel J; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104.
  • Doerger E; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
  • Renner DM; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045.
  • Tan LH; Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045.
  • Perlman S; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104.
  • Cohen NA; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
  • Fehr AR; Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA 19104.
  • Weiss SR; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242.
Proc Natl Acad Sci U S A ; 119(21): e2123208119, 2022 05 24.
Article in English | MEDLINE | ID: covidwho-1860508
ABSTRACT
Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into humans in 2012, causing highly lethal respiratory disease. The severity of disease may be, in part, because MERS-CoV is adept at antagonizing early innate immune pathways­interferon (IFN) production and signaling, protein kinase R (PKR), and oligoadenylate synthetase/ribonuclease L (OAS/RNase L)­activated in response to viral double-stranded RNA (dsRNA) generated during genome replication. This is in contrast to severe acute respiratory syndrome CoV-2 (SARS-CoV-2), which we recently reported to activate PKR and RNase L and, to some extent, IFN signaling. We previously found that MERS-CoV accessory proteins NS4a (dsRNA binding protein) and NS4b (phosphodiesterase) could weakly suppress these pathways, but ablation of each had minimal effect on virus replication. Here we investigated the antagonist effects of the conserved coronavirus endoribonuclease (EndoU), in combination with NS4a or NS4b. Inactivation of EndoU catalytic activity alone in a recombinant MERS-CoV caused little if any effect on activation of the innate immune pathways during infection. However, infection with recombinant viruses containing combined mutations with inactivation of EndoU and deletion of NS4a or inactivation of the NS4b phosphodiesterase promoted robust activation of dsRNA-induced innate immune pathways. This resulted in at least tenfold attenuation of replication in human lung­derived A549 and primary nasal cells. Furthermore, replication of these recombinant viruses could be rescued to the level of wild-type MERS-CoV by knockout of host immune mediators MAVS, PKR, or RNase L. Thus, EndoU and accessory proteins NS4a and NS4b together suppress dsRNA-induced innate immunity during MERS-CoV infection in order to optimize viral replication.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Coronavirus Infections / Middle East Respiratory Syndrome Coronavirus / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Coronavirus Infections / Middle East Respiratory Syndrome Coronavirus / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2022 Document Type: Article