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Review
. 2018 Aug 12;10(8):423.
doi: 10.3390/v10080423.

A Systems Approach to Study Immuno- and Neuro-Modulatory Properties of Antiviral Agents

Eva Zusinaite  1 , Aleksandr Ianevski  2 , Diana Niukkanen  3 , Minna M Poranen  4 , Magnar Bjørås  5   6 , Jan Egil Afset  7 , Tanel Tenson  8 , Vidya Velagapudi  9 , Andres Merits  10 , Denis E Kainov  11   12
Affiliations
Review

A Systems Approach to Study Immuno- and Neuro-Modulatory Properties of Antiviral Agents

Eva Zusinaite et al. Viruses. .

Abstract

There are dozens of approved, investigational and experimental antiviral agents. Many of these agents cause serious side effects, which can only be revealed after drug administration. Identification of the side effects prior to drug administration is challenging. Here we describe an ex vivo approach for studying immuno- and neuro-modulatory properties of antiviral agents, which may be associated with potential side effects of these therapeutics. The current approach combines drug toxicity/efficacy tests and transcriptomics, which is followed by mRNA, cytokine and metabolite profiling. We demonstrated the utility of this approach with several examples of antiviral agents. We also showed that the approach can utilize different immune stimuli and cell types. It can also include other omics techniques, such as genomics and epigenomics, to allow identification of individual markers associated with adverse reactions to antivirals with immuno- and neuro-modulatory properties.

Keywords: antiviral agent; drug side effect; drug target; innate immunity; precision medicine; systems biology; virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Eye diagram linking antiviral agents (middle) with their side effects (left) and targets (right). The information on drug targets and side effects were retrieved from DrugBank (www.drugbank.ca). Antiviral agents with four or more links to targets or side effects are shown.
Figure 2
Figure 2
Systems approach to study immuno- and neuro-modulatory properties of antiviral agents.
Figure 3
Figure 3
SaliPhe, SNS-032, obatoclax and gemcitabine differentially affect transcription of immune-related genes in stimulated human PBMC-derived macrophages. The macrophages were treated with 3 μM SaliPhe, 0.1 μM SNS-032, 2 μM obatoclax, 1 μM gemcitabine or remained non-treated and infected with IAV (moi 1), or stimulated with 1 μg/mL dsRNA, 1 μg/mL LPS, 1 U/mL IFN-α, or remained non-stimulated. After 8 h, cells were collected; total RNA was extracted and subjected to genome-wide gene expression analysis. Genes, which relative expression levels were up- or down-regulated (log2FC(stimulus_no drug–mock_no drug) > 3 and <−3) in response to stimuli in drug non-treated cells, are indicated with orange curves. Genes, which relative expression levels were up- or down-regulated in response to drug treatment in stimulated cells, are shown with green curves (log2FC(stimulus_drug–stimulus_no drug) > 3 and <−3). The size of the red and blue circles corresponds to fold changes in expression levels of genes.
Figure 4
Figure 4
SaliPhe, SNS-032, obatoclax and gemcitabine differentially affect levels of cytokines and growth factors in the culture media of human PBMC-derived macrophages. PBMC-derived macrophages were treated with 3 μM SaliPhe, 0.1 μM SNS-032, 2 μM obatoclax, 1 μM gemcitabine or remained non-treated and infected with IAV (moi 1), or stimulated with 1 μg/mL dsRNA, 1 μg/mL LPS, 1 U/mL IFN-α, or remained non-stimulated. After 24 h, cell culture media were collected and 105 secreted proteins were subjected to analysis with human XL cytokine array kit. Soluble proteins, which relative levels were up- or down-regulated in response to stimuli in the media of non-treated cells, are indicated with orange curves. Soluble proteins, which relative levels were up- or down-regulated in response to stimuli in the media of drug-treated cells, are indicated with green curves.
Figure 5
Figure 5
SaliPhe, SNS-032, obatoclax and gemcitabine, differentially affect levels of several polar metabolites in the culture media from stimulated PBMC-derived macrophages. PBMC-derived macrophages were treated with 3 μM SaliPhe, 0.1 μM SNS-032, 2 μM obatoclax, 1 μM gemcitabine or remained non-treated and infected with IAV (moi 1), or stimulated with 1 μg/mL dsRNA, 1 μg/mL LPS, 1 U/mL IFN-α, or remained non-stimulated. After 24 h, cell culture media were collected; polar metabolites were extracted and subjected to targeted metabolomics analysis. Metabolites, which levels were up- or down-regulated (log2FC(stimulus_no drug–mock_no drug) > 1.5 and <−1.5) in response to stimuli in the media of drug non-treated cells, are indicated with orange curves. Metabolites, which levels were up- or down-regulated (log2FC(stimulus_drug–stimulus_no drug) > 1.5 and <−1.5) in response to drug treatment in the media of activated cells, are shown in green. The size of the red and blue circles corresponds to fold changes in the level of metabolites.
Figure 6
Figure 6
Added value of the systems approach. Systems approaches will guide the evaluation of novel antivirals and their side effects and implementation into personalized medicine pipeline.
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