Stress granule-inducing eukaryotic translation initiation factor 4A inhibitors block influenza A virus replication

Patrick D. Slaine, Mariel Kleer, Nathan K. Smith, Denys A. Khaperskyy, Craig McCormick

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41 Citas (Scopus)

Resumen

Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5′ untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection resulted in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible, drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates that the core host protein synthesis machinery can be targeted to block viral replication.

Idioma originalEnglish
Número de artículo388
PublicaciónViruses
Volumen9
N.º12
DOI
EstadoPublished - dic. 18 2017

Nota bibliográfica

Funding Information:
Acknowledgments: We thank Brett Duguay and members of the McCormick lab for critical reading of the manuscript. We thank Kevin Coombs (University of Manitoba, Winnipeg, MB, Canada), Yoshihiro Kawaoka (University of Wisconsin-Madison, Madison, WI, USA), Jerry Pelletier (McGill University, Montreal, QC, Canada), and Richard Webby (St. Jude Children’s Hospital, Memphis, TN, USA) for reagents. We thank Stephen Whitefield at the Dalhousie University Faculty of Medicine Cellular & Molecular Digital Imaging Core Facility for microscopy support. This work was supported by CIHR Operating Grants MOP-136817 and PJT 148727, and NSERC Discovery Grant RGPIN/341940-2012.

Publisher Copyright:
© 2017 by the authors. Licensee MDPI, Basel, Switzerland.

ASJC Scopus Subject Areas

  • Infectious Diseases
  • Virology

PubMed: MeSH publication types

  • Journal Article

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