Critical Nodes of Virus–Host Interaction Revealed Through an Integrated Network Analysis

Korbinian Bösl; Aleksandr Ianevski; Thoa T. Than; Petter I. Andersen; Suvi Kuivanen; Mona Teppor; Eva Zusinaite; Uga Dumpis; Astra Vitkauskiene; Rebecca J. Cox; Hannimari Kallio-Kokko; Anders Bergqvist; Tanel Tenson; Valentyn Oksenych; Magnar Bjørås; Marit W. Anthonsen; David Shum; Mari Kaarbø; Olli Vapalahti; Marc P. Windisch; Giulio Superti-Furga; Berend Snijder; Denis Kainov; Richard K. Kandasamy

We found that host targets from the hvPPI were spread across the spectrum of genes with proviral as well as antiviral phenotype (Fig. S5) , thus showing that targeting of the host protein by the virus could lead into any direction that favours the virus. We then investigated the top 50 proviral genes that are also targeted by the viral proteins as seen in the hvPPI. We identified 42 host proteins (Fig. 5A ) that were significantly enriched for coatomer protein complex 1 (COPI), protein translation/transport and proteasome (Fig. 5B) . This further substantiates the findings from the earlier section on the core cellular processes targeted by the viruses. Network analysis of these top hits showed high level on connectivity and crosstalk -for example between the translation and proteasome machinery (Fig. 5C ). Vesicle carriers are involved in the transport of membranes and proteins. COPI system is one of the three vesicular carrier systems that is involved in the early secretory pathway (Beck et al. 2009 , Lee et al. 2004 , Bethune et al. 2006 . Moreover, it has been pointed out that there is a strong similarity between vesicular transport and viral transport (viral entry to budding process) (Thaa et al. 2010) ; thus making COPI system important for the viral life cycle. SiRNAbased silencing of COPI lead to a defect in entry of IAV and disruption of the COPI complex inhibited the production of infectious progeny virus (Sun et al. 2013) . Altogether, these top hits including the COPI system could serve as targets for developing therapeutic antiviral intervention strategies for a broad group of viruses.