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.
Highlights
The Orthomyxoviridae family member influenza A virus is the causal agent of acute respiratory tract infections suffered annually by 5–20% of the human population
We found that 100% of HBEC30 in culture display viral protein production after a 24-hour exposure to mouse-adapted virus at an MOI of 5 (Figure 1A, B)
Raw viability values were converted to viability Z-scores with a metric that normalized for both position and batch effects (Figure 1D, see methods)
Summary
The Orthomyxoviridae family member influenza A virus is the causal agent of acute respiratory tract infections suffered annually by 5–20% of the human population. We have employed the cytopathic effects of H1N1 infection in bronchial epithelial cells as a mechanism to isolate host genes that represent intervention target opportunities by virtue of their contribution to H1N1 infection and replication, or by virtue of their contribution to viral virulence factor-dependent evasion of innate immune responses. A primary whole-genome arrayed siRNA screen identified gene depletions that either deflected or promoted bronchial epithelial cell death upon exposure to the H1N1 A/WSN/33 influenza virus and were not cytotoxic to mock infected cells.
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