The COVID-19 disease led to an unprecedented health emergency, still ongoing worldwide. Given the lack of a vaccine or a clear therapeutic strategy to counteract the infection as well as its secondary effects, there is currently a pressing need to generate new insights into the SARS-CoV-2 induced host response. Biomedical data can help to investigate new aspects of the COVID-19 pathogenesis, but source heterogeneity represents a major drawback and limitation. In this work, we applied data integration methods to develop a Unified Knowledge Space (UKS) and used it to identify a new set of genes associated with SARS-CoV-2 host response, both in vitro and in vivo. Functional analysis of these genes reveals possible long-term systemic effects of the infection, such as vascular remodelling and fibrosis. Finally, we identified a set of potentially relevant drugs targeting proteins involved in multiple steps of the host response to the virus.

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Background Omics technologies have been widely applied in toxicology studies to investigate the effects of different substances on exposed biological systems. A classical toxicogenomic study consists in testing the effects of a compound at different dose levels and different time points. The main challenge consists in identifying the gene alteration patterns that are correlated to doses and time points. The majority of existing methods for toxicogenomics data analysis allow the study of the molecular alteration after the exposure (or treatment) at each time point individually. However, this kind of analysis cannot identify dynamic (time-dependent) events of dose responsiveness. Results We propose TinderMIX, an approach that simultaneously models the effects of time and dose on the transcriptome to investigate the course of molecular alterations exerted in response to the exposure. Starting from gene log fold-change, TinderMIX fits different integrated time and dose models to each gene, selects the optimal one, and computes its time and dose effect map; then a user-selected threshold is applied to identify the responsive area on each map and verify whether the gene shows a dynamic (time-dependent) and dose-dependent response; eventually, responsive genes are labelled according to the integrated time and dose point of departure. Conclusions To showcase the TinderMIX method, we analysed 2 drugs from the Open TG-GATEs dataset, namely, cyclosporin A and thioacetamide. We first identified the dynamic dose-dependent mechanism of action of each drug and compared them. Our analysis highlights that different time- and dose-integrated point of departure recapitulates the toxicity potential of the compounds as well as their dynamic dose-dependent mechanism of action.

Mechanistic toxicology provides a powerful approach to inform on the safety of chemicals and the development of safe‐by‐design compounds. Although toxicogenomics supports mechanistic evaluation of chemical exposures, its implementation into the regulatory framework is hindered by uncertainties in the analysis and interpretation of such data. The use of mechanistic evidence through the adverse outcome pathway (AOP) concept is promoted for the development of new approach methodologies (NAMs) that can reduce animal experimentation. However, to unleash the full potential of AOPs and build confidence into toxicogenomics, robust associations between AOPs and patterns of molecular alteration need to be established. Systematic curation of molecular events to AOPs will create the much‐needed link between toxicogenomics and systemic mechanisms depicted by the AOPs. This, in turn, will introduce novel ways of benefitting from the AOPs, including predictive models and targeted assays, while also reducing the need for multiple testing strategies. Hence, a multi‐step strategy to annotate AOPs is developed, and the resulting associations are applied to successfully highlight relevant adverse outcomes for chemical exposures with strong in vitro and in vivo convergence, supporting chemical grouping and other data‐driven approaches. Finally, a panel of AOP‐derived in vitro biomarkers for pulmonary fibrosis (PF) is identified and experimentally validated.