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

Abstract

Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve the maximal effect by targeting multifunctional and highly connected host proteins with a high occurrence of disordered regions. We also identified the core cellular process subnetworks that are targeted by all the viruses. Integration with functional RNA interference (RNAi) datasets showed that a large proportion of the targets are required for viral replication. Furthermore, we performed an interactome-informed drug re-purposing screen and identified novel activities for broad-spectrum antiviral agents against hepatitis C virus and human metapneumovirus. Altogether, these orthogonal datasets could serve as a platform for hypothesis generation and follow-up studies to broaden our understanding of the viral evasion landscape.

Discovery and development of safe-in-man broad-spectrum antiviral agents

“…Other cell death assays include LDH enzyme leakage assays, membrane impermeable dye-based assays, and apoptosis assays, such as Annexin V, TUNEL, and caspase assays (Shen et al, 2019). For example, the Cell Titer Glo (CTG) assay quantifies ATP, an indicator of metabolically active living cells, whereas Cell Tox Green assay uses fluorescent asymmetric cyanine dye that stains the DNA of dead cells (Bosl et al, 2019;Bulanova et al, 2017;Ianevski et al, 2018;Muller et al, 2014). Viral strains or cell lines expressing reporter proteins are also used to assess the efficacy of BSAAs in infected cells.…”

“…For example, TZM-bl cells expressing firefly luciferase under control of HIV-1 LTR promoter allowed quantitation of BSAA action on HIV-1 infection (tat-protein expression by integrated HIV-1 provirus) using firefly luciferase assay (Sarzotti-Kelsoe et al, 2014;Xing et al, 2016). RFPexpressing RVFV, nanoLuc-expressing CHIKV and RRV, as well as GFP-expressing FLUAV, HCV and HMPV also allowed identification of novel activities of several BSAAs (Andersen et al, 2019b;Bosl et al, 2019;de Graaf et al, 2007;Habjan et al, 2008;Ianevski et al, 2018;Jupille et al, 2011;Kittel et al, 2004;Lee et al, 2017;Utt et al., 2016). In addition, qPCR/RT-qPCR, RNA/DNA sequencing, RNA/DNA hybridization, immuno-and plaque assays as well as CRISPR-CAS9 systems could be used for detection of inhibitory effects of BSAAs (Boonham et al, 2014;Fischer et al, 2017;Konig et al, 2019;Laamiri et al, 2018;Landry, 1990;Perez et al, 2013;Sashital, 2018;Zhou et al, 2018).…”

“…A counterpoint to this is "one drug, multiple viruses" paradigm, which came with the discovery of broad-spectrum antiviral agents (BSAAs), small-molecules that inhibit a wide range of human viruses (Bekerman and Einav, 2015;de Clercq and Montgomery, 1983;Debing et al, 2015;Ianevski et al, 2019;Rada and Dragun, 1977;Sidwell et al, 1972). This paradigm was based on the observation that different viruses utilize similar pathways and host factors to replicate inside a cell (Bosl et al, 2019). Although the concept of BSAAs has been around for almost 50 years, the field received a new impetus with recent outbreaks of Ebola, Zika, Dengue, influenza and other viral infections, the discovery of novel host-directed agents as well as development of drug repositioning methodology.Drug repurposing, also called repositioning, redirecting, reprofiling, is a strategy for generating additional value from an existing drug by targeting disease other than that for which it was originally intended (Nishimura and Hara, 2018;Pushpakom et al, 2019).…”

Drug repurposing strategies for COVID-19

“…Andersen et al have recently summarized 31 potential candidates for COVID-19 in a highly accessible database of 120 experimental, investigational and approved agents [2]. Conceptually, BSAAs take advantage of the promiscuity of viral replicative mechanisms and host interactions to target two or more viral families [3]. Following the COVID-19 outbreak in December 2019, a few existing BSAAs have been rapidly introduced into clinical trials, spanning Phases II though IV.…”

“…One way to circumvent this issue is to evaluate two or more drugs acting on different cellular signaling pathways involving viral replication with minimal redundancy. Another strategy is high-throughput screening of compound libraries for synergistic combinations at the host-virus interactome level for emerging and re-emerging infectious diseases, which may allow researchers to narrow down the spectrum of individual antimicrobials [3,12,13]. These strategies promise to address the often-weak activity of BSAAs by improving efficacy while potentiating dose reductions, reducing duration, cost of the drug development pipeline, lowering toxicity and minimizing emergence of secondary resistance.…”