The use of Random Homozygous Gene Perturbation to identify novel host-oriented targets for influenza

Baoquan Sui, Douty Bamba, Ke Weng, Huong Ung, Shaojing Chang, Jessica Van Dyke, Michael Goldblatt, Roxanne Duan, Michael S. Kinch, Wu Bo Li

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Conventional approaches for therapeutic targeting of viral pathogens have consistently faced obstacles arising from the development of resistant strains and a lack of broad-spectrum application. Influenza represents a particularly problematic therapeutic challenge since high viral mutation rates have often confounded many conventional antivirals. Newly emerging or engineered strains of influenza represent an even greater threat as typified by recent interest in avian subtypes of influenza. Based on the limitations associated with targeting virally-encoded molecules, we have taken an orthogonal approach of targeting host pathways in a manner that prevents viral propagation or spares the host from virus-mediated pathogenicity. To this end, we report herein the application of an improved technology for target discovery, Random Homozygous Gene Perturbation (RHGP), to identify host-oriented targets that are well-tolerated in normal cells but that prevent influenza-mediated killing of host cells. Improvements in RHGP facilitated a thorough screening of the entire genome, both for overexpression or loss of expression, to identify targets that render host cells resistant to influenza infection. We identify a set of host-oriented targets that prevent influenza killing of host cells and validate these targets using multiple approaches. These studies provide further support for a new paradigm to combat viral disease and demonstrate the power of RHGP to identify novel targets and mechanisms.

Original languageEnglish
Pages (from-to)473-481
Number of pages9
JournalVirology
Volume387
Issue number2
DOIs
StatePublished - May 10 2009

Keywords

  • Host-oriented therapeutics
  • Influenza
  • RHGP

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