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

doi:10.1371/journal.pone.0039284

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Host modulators of H1N1 cytopathogenicity

Journal article

Open access

Peer reviewed

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, …

PloS one, Vol.7(8), pp.e39284-e39284

2012

DOI: 10.1371/journal.pone.0039284

PMCID: PMC3410888

PMID: 22876275

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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.

Animals

Cell Line

Cluster Analysis

Cytopathogenic Effect, Viral

Epithelial Cells - virology

Gene Expression Profiling

Gene Regulatory Networks

Host-Pathogen Interactions - genetics

Humans

Influenza A Virus, H1N1 Subtype - drug effects

Influenza A Virus, H1N1 Subtype - physiology

Lactates - pharmacology

Molecular Sequence Annotation

Organophosphonates - pharmacology

Respiratory Mucosa - virology

RNA Interference

Virus Replication

Details

Title: Subtitle: Host modulators of H1N1 cytopathogenicity
Creators: Samuel E Ward - Department of Cell Biology, University of Texas Southwestern Medical School, Dallas, Texas, United States of America
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 - The University of Texas Southwestern Medical Center
Resource Type: Journal article
Publication Details: PloS one, Vol.7(8), pp.e39284-e39284
DOI: 10.1371/journal.pone.0039284
PMID: 22876275
PMCID: PMC3410888
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Grant note: K99 AI095320 / NIAID NIH HHS CA129451 / NCI NIH HHS AI083614 / NIAID NIH HHS R21 AI083614 / NIAID NIH HHS AI095320 / NIAID NIH HHS P30 CA142543 / NCI NIH HHS R01 CA129451 / NCI NIH HHS CA071443 / NCI NIH HHS R01 AI079110 / NIAID NIH HHS R01 AI089539 / NIAID NIH HHS R00 AI095320 / NIAID NIH HHS R01 CA071443 / NCI NIH HHS HHSN266200700010C / NIAID NIH HHS
Language: English
Date published: 2012
Academic Unit: Microbiology and Immunology
Record Identifier: 9984208257102771

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