Host factor prioritization for pan-viral genetic perturbation screens using random intercept models and network propagation

PLoS Comput Biol. 2020 Feb 10;16(2):e1007587. doi: 10.1371/journal.pcbi.1007587. eCollection 2020 Feb.

Abstract

Genetic perturbation screens using RNA interference (RNAi) have been conducted successfully to identify host factors that are essential for the life cycle of bacteria or viruses. So far, most published studies identified host factors primarily for single pathogens. Furthermore, often only a small subset of genes, e.g., genes encoding kinases, have been targeted. Identification of host factors on a pan-pathogen level, i.e., genes that are crucial for the replication of a diverse group of pathogens has received relatively little attention, despite the fact that such common host factors would be highly relevant, for instance, for devising broad-spectrum anti-pathogenic drugs. Here, we present a novel two-stage procedure for the identification of host factors involved in the replication of different viruses using a combination of random effects models and Markov random walks on a functional interaction network. We first infer candidate genes by jointly analyzing multiple perturbations screens while at the same time adjusting for high variance inherent in these screens. Subsequently the inferred estimates are spread across a network of functional interactions thereby allowing for the analysis of missing genes in the biological studies, smoothing the effect sizes of previously found host factors, and considering a priori pathway information defined over edges of the network. We applied the procedure to RNAi screening data of four different positive-sense single-stranded RNA viruses, Hepatitis C virus, Chikungunya virus, Dengue virus and Severe acute respiratory syndrome coronavirus, and detected novel host factors, including UBC, PLCG1, and DYRK1B, which are predicted to significantly impact the replication cycles of these viruses. We validated the detected host factors experimentally using pharmacological inhibition and an additional siRNA screen and found that some of the predicted host factors indeed influence the replication of these pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Regulatory Networks*
  • Genes, Viral
  • Host Microbial Interactions / genetics*
  • Models, Biological*
  • RNA Interference
  • Viruses / genetics*

Grants and funding

This work has been funded by ERASysAPP, the ERA-Net for Applied Systems Biology, under grant ERASysAPP-30 (SysVirDrug). ERASysAPP had no role in data collection, analysis or preparation of the manuscript.