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Journal of virology
04 01, 2018;92 (7):

Specific Mutations in the PB2 Protein of Influenza A Virus Compensate for the Lack of Efficient Interferon Antagonism of the NS1 Protein of Bat Influenza A-Like Viruses.

Teresa Aydillo, Juan Ayllon, Amzie Pavlisin, Carles Martinez-Romero, Shashank Tripathi, Ignacio Mena, Andrés Moreira-Soto, Amanda Vicente-Santos, Eugenia Corrales-Aguilar, Martin Schwemmle, Adolfo García-Sastre
Author Information
  1. Teresa Aydillo: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  2. Juan Ayllon: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  3. Amzie Pavlisin: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  4. Carles Martinez-Romero: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  5. Shashank Tripathi: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  6. Ignacio Mena: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  7. Andrés Moreira-Soto: Virology-CIET, Faculty of Microbiology, University of Costa Rica, San José, Costa Rica.
  8. Amanda Vicente-Santos: Virology-CIET, Faculty of Microbiology, University of Costa Rica, San José, Costa Rica.
  9. Eugenia Corrales-Aguilar: Virology-CIET, Faculty of Microbiology, University of Costa Rica, San José, Costa Rica.
  10. Martin Schwemmle: Institute of Virology, Medical Center, University of Freiburg, Freiburg, Germany.
  11. Adolfo García-Sastre: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA Adolfo.Garcia-Sastre@mssm.edu.
PMID: 29321309 DOI: 10.1128/JVI.02021-17

Abstract

Recently, two new influenza A-like viruses have been discovered in bats, A/little yellow-shouldered bat/Guatemala/060/2010 (HL17NL10) and A/flat-faced bat/Peru/033/2010 (HL18NL11). The hemagglutinin (HA)-like (HL) and neuraminidase (NA)-like (NL) proteins of these viruses lack hemagglutination and neuraminidase activities, despite their sequence and structural homologies with the HA and NA proteins of conventional influenza A viruses. We have now investigated whether the NS1 proteins of the HL17NL10 and HL18NL11 viruses can functionally replace the NS1 protein of a conventional influenza A virus. For this purpose, we generated recombinant influenza A/Puerto Rico/8/1934 (PR8) H1N1 viruses containing the NS1 protein of the PR8 wild-type, HL17NL10, and HL18NL11 viruses. These viruses (r/NS1PR8, r/NS1HL17, and r/NS1HL18, respectively) were tested for replication in bat and nonbat mammalian cells and in mice. Our results demonstrate that the r/NS1HL17 and r/NS1HL18 viruses are attenuated and However, the bat NS1 recombinant viruses showed a phenotype similar to that of the r/NS1PR8 virus in STAT1 human A549 cells and mice, both and systems being unable to respond to interferon (IFN). Interestingly, multiple mouse passages of the r/NS1HL17 and r/NS1HL18 viruses resulted in selection of mutant viruses containing single amino acid mutations in the viral PB2 protein. In contrast to the parental viruses, virulence and IFN antagonism were restored in the selected PB2 mutants. Our results indicate that the NS1 protein of bat influenza A-like viruses is less efficient than the NS1 protein of its conventional influenza A virus NS1 counterpart in antagonizing the IFN response and that this deficiency can be overcome by the influenza virus PB2 protein. Significant gaps in our understanding of the basic features of the recently discovered bat influenza A-like viruses HL17NL10 and HL18NL11 remain. The basic biology of these unique viruses displays both similarities to and differences from the basic biology of conventional influenza A viruses. Here, we show that recombinant influenza A viruses containing the NS1 protein from HL17NL10 and HL18NL11 are attenuated. This attenuation was mediated by their inability to antagonize the type I IFN response. However, this deficiency could be compensated for by single amino acid replacements in the PB2 gene. Our results unravel a functional divergence between the NS1 proteins of bat influenza A-like and conventional influenza A viruses and demonstrate an interplay between the viral PB2 and NS1 proteins to antagonize IFN.

Keywords

NS1 protein bat influenza viruses interferons

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Grants

  1. HHSN272201400008C/NIAID NIH HHS

MeSH Term

A549 Cells
HEK293 Cells
Humans
Influenza A virus
Interferons
Mutation
Viral Nonstructural Proteins
Viral Proteins

Chemicals

INS1 protein, influenza virus
PB2 protein, influenza virus
Viral Nonstructural Proteins
Viral Proteins
Interferons
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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