Activation of RNase L by murine coronavirus in myeloid cells is dependent on basal Oas gene expression and independent of virus-induced interferon

L. Dillon Birdwell, Zachary B. Zalinger, Yize Li, Patrick W. Wright, Ruth Elliott, Kristine M. Rose, Robert H. Silverman, Susan R. Weiss

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The oligoadenylate synthetase (OAS)-RNase L pathway is a potent interferon (IFN)-induced antiviral activity. Upon sensing double-stranded RNA, OAS produces 2',5'-oligoadenylates (2-5A), which activate RNase L. Murine coronavirus (mouse hepatitis virus [MHV]) nonstructural protein 2 (ns2) is a 2',5'-phosphodiesterase (PDE) that cleaves 2-5A, thereby antagonizing RNase L activation. PDE activity is required for robust replication in myeloid cells, as a mutant of MHV (ns2H126R) encoding an inactive PDE fails to antagonize RNase L activation and replicates poorly in bone marrow-derived macrophages (BMM), while ns2H126R replicates to high titer in several types of nonmyeloid cells, as well as in IFN receptor-deficient (Ifnar1-/-) BMM. We reported previously that myeloid cells express significantly higher basal levels of OAS transcripts than nonmyeloid cells. Here, we investigated the contributions of Oas gene expression, basal IFN signaling, and virus-induced IFN to RNase L activation. Infection with ns2H126R activated RNase L in Ifih1-/- BMM to a similar extent as in wild-type (WT) BMM, despite the lack of IFN induction in the absence of MDA5 expression. However, ns2H126R failed to induce RNase L activation in BMM treated with IFNAR1-blocking antibody, as well as in Ifnar1-/- BMM, both expressing low basal levels of Oas genes. Thus, activation of RNase L does not require virus-induced IFN but rather correlates with adequate levels of basal Oas gene expression, maintained by basal IFN signaling. Finally, overexpression of RNase L is not sufficient to compensate for inadequate basal OAS levels.

Original languageEnglish (US)
Pages (from-to)3160-3172
Number of pages13
JournalJournal of virology
Volume90
Issue number6
DOIs
StatePublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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