Host modulators of H1N1 cytopathogenicity

Samuel E. Ward, Hyun Seok Kim, Kakajan Komurov, Saurabh Mendiratta, Pei Ling Tsai, Mirco Schmolke, Neal Satterly, Balaji Manicassamy, Christian V. Forst, Michael G. Roth, Adolfo García-Sastre, Katarzyna M. Blazewska, Charles E. McKenna, Beatriz M. Fontoura, Michael A. White

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Influenza A virus infects 5-20% of the population annually, resulting in ~35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors.

Original languageEnglish (US)
Article numbere39284
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 2 2012

Fingerprint

cytopathogenicity
viral proteins
Viral Proteins
Viruses
Modulators
epithelial cells
Epithelial Cells
Influenza A virus
Vaccines
Genes
infection
vaccines
H1N1 Subtype Influenza A Virus
suicide
drug resistance
Pandemics
Virulence Factors
pandemic
Virus Diseases
small interfering RNA

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ward, S. E., Kim, H. S., Komurov, K., Mendiratta, S., Tsai, P. L., Schmolke, M., ... White, M. A. (2012). Host modulators of H1N1 cytopathogenicity. PLoS One, 7(8), [e39284]. https://doi.org/10.1371/journal.pone.0039284

Host modulators of H1N1 cytopathogenicity. / Ward, Samuel E.; Kim, Hyun Seok; Komurov, Kakajan; Mendiratta, Saurabh; Tsai, Pei Ling; Schmolke, Mirco; Satterly, Neal; Manicassamy, Balaji; Forst, Christian V.; Roth, Michael G.; García-Sastre, Adolfo; Blazewska, Katarzyna M.; McKenna, Charles E.; Fontoura, Beatriz M.; White, Michael A.

In: PLoS One, Vol. 7, No. 8, e39284, 02.08.2012.

Research output: Contribution to journalArticle

Ward, SE, Kim, HS, Komurov, K, Mendiratta, S, Tsai, PL, Schmolke, M, Satterly, N, Manicassamy, B, Forst, CV, Roth, MG, García-Sastre, A, Blazewska, KM, McKenna, CE, Fontoura, BM & White, MA 2012, 'Host modulators of H1N1 cytopathogenicity', PLoS One, vol. 7, no. 8, e39284. https://doi.org/10.1371/journal.pone.0039284
Ward SE, Kim HS, Komurov K, Mendiratta S, Tsai PL, Schmolke M et al. Host modulators of H1N1 cytopathogenicity. PLoS One. 2012 Aug 2;7(8). e39284. https://doi.org/10.1371/journal.pone.0039284
Ward, Samuel E. ; Kim, Hyun Seok ; Komurov, Kakajan ; Mendiratta, Saurabh ; Tsai, Pei Ling ; Schmolke, Mirco ; Satterly, Neal ; Manicassamy, Balaji ; Forst, Christian V. ; Roth, Michael G. ; García-Sastre, Adolfo ; Blazewska, Katarzyna M. ; McKenna, Charles E. ; Fontoura, Beatriz M. ; White, Michael A. / Host modulators of H1N1 cytopathogenicity. In: PLoS One. 2012 ; Vol. 7, No. 8.
@article{a83ac2a1d4c54cd2b3fe3e9a94251263,
title = "Host modulators of H1N1 cytopathogenicity",
abstract = "Influenza A virus infects 5-20{\%} of the population annually, resulting in ~35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors.",
author = "Ward, {Samuel E.} and Kim, {Hyun Seok} and Kakajan Komurov and Saurabh Mendiratta and Tsai, {Pei Ling} and Mirco Schmolke and Neal Satterly and Balaji Manicassamy and Forst, {Christian V.} and Roth, {Michael G.} and Adolfo Garc{\'i}a-Sastre and Blazewska, {Katarzyna M.} and McKenna, {Charles E.} and Fontoura, {Beatriz M.} and White, {Michael A.}",
year = "2012",
month = "8",
day = "2",
doi = "10.1371/journal.pone.0039284",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Host modulators of H1N1 cytopathogenicity

AU - Ward, Samuel E.

AU - Kim, Hyun Seok

AU - Komurov, Kakajan

AU - Mendiratta, Saurabh

AU - Tsai, Pei Ling

AU - Schmolke, Mirco

AU - Satterly, Neal

AU - Manicassamy, Balaji

AU - Forst, Christian V.

AU - Roth, Michael G.

AU - García-Sastre, Adolfo

AU - Blazewska, Katarzyna M.

AU - McKenna, Charles E.

AU - Fontoura, Beatriz M.

AU - White, Michael A.

PY - 2012/8/2

Y1 - 2012/8/2

N2 - Influenza A virus infects 5-20% of the population annually, resulting in ~35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors.

AB - Influenza A virus infects 5-20% of the population annually, resulting in ~35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors.

UR - http://www.scopus.com/inward/record.url?scp=84864442238&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864442238&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0039284

DO - 10.1371/journal.pone.0039284

M3 - Article

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e39284

ER -