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Increased susceptibility to viral entry and coronavirus production leading to thrombosis and disseminated intravascular coagulation: International joint research project for development of Adverse Outcome Pathway (AOP)
Citation:
Tanabe, S., Y. Kim, A. Paini, S. Mayasich, M. Amorim, N. Parissis, P. Nymark, M. Martens, D. Jacobson, F. Gavins, L. Margiotta-Casaluci, S. Halappanavar, N. Garcia-Reyero, J. Filipovska, S. Edwards, R. Ram, A. Layton, B. Landesmann, H. Yepiskoposyan, J. Sund, C. Wittwehr, AND L. Clerbaux. Increased susceptibility to viral entry and coronavirus production leading to thrombosis and disseminated intravascular coagulation: International joint research project for development of Adverse Outcome Pathway (AOP). 11th Annual Meeting of Society for Regulatory Science of Medical Products, Tokyo, JAPAN, September 17, 2021. https://doi.org/10.23645/epacomptox.16896781
Impact/Purpose:
The Adverse Outcome Pathway (AOP) framework developed for use in the field of toxicology has come into widespread use by many organizations, and other applications of the AOP framework have emerged. The European Commission – Joint Research Council has initiated a crowdsourced project (called CIAO) to utilize the AOP framework to organize and interpret the massive ongoing efforts by researchers to characterize the COVID-19 disease caused by the SARS-CoV-2 virus. An AOP that characterizes the early events from increased susceptibility and viral replication to thrombosis has been accepted as a joint project with the Organization for Economic Co-operation and Development (OECD), which is an exciting step forward in this international collaboration. Having studies such as this presented at various scientific meetings elevates the work of CIAO to expand the crowd with more experts as well as continuing to promote worldwide visibility of the AOP framework.
Description:
The emergence of new diseases poses an international threat, and the pathological mechanism and side effects of developed drugs are potentially harmful. Predicting and evaluating safety has become a common international issue in pharmaceutical administration. Based on the fact that elucidation and prediction of hazards of pharmaceutical products have become common international issues, the hazard manifestation route (pathological mechanism) was investigated. Due to the international progress in advancing the Adverse Outcome Pathway (AOP) framework for a variety of applications, an AOP is being developed considering the new coronavirus. The purpose was to elucidate the pathological mechanism network of infectious diseases using literature research and in silico analyses. [Method] Gene expression analysis of microarray data and RNAseq data on the Gene Expression Omnibus (GEO) database was performed. Additionally, an ingenuity molecular network analysis was performed using the Ingenuity Pathway Analysis (IPA) application. To elucidate the molecular network related to the new coronavirus infection, gene expression data of SARS-CoV-2 infected cells were displayed on the coronavirus infection pathological pathway. The International Joint Research Project CIAO (Modeling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway Framework) consisting of experts from various countries, developed an AOP describing the new coronavirus infection. [Result] Analysis of gene expression data on the GEO database showed the expression of genes including EIF2AK3 and FOS on the pathway is increased by new coronavirus infection. Molecules such as IL6, FASLG, and CCL2 indicate viral pathology was activated, with reactive oxygen species production and oxidative stress response. Molecules associated with blood clotting were also mapped. In addition, literature research has shown that oxidative stress response and the pathway from blood clotting to thrombus formation are involved in progression of infection. [Discussion] Based on the discussions at CIAO and these results, an AOP is being co-developed with the OECD (Organization for Economic Co-operation and Development) that considers increased susceptibility to coronavirus infection and virus production leading to thrombus formation. Extreme hypercoagulability causes excessive thrombus formation in microvessels. It is thought that depletion of blood coagulation factors causes consumption coagulopathy, that is, disseminated intravascular coagulation. Therefore, this mechanism may be related to the severity of new coronavirus infections. [Conclusion] As part of the elucidation of the pathological mechanism of the new coronavirus infection, SARS-CoV-2, reactive oxygen species and oxidative stress response associated with cell infection and involvement of blood coagulation pathways have been suggested. Progress has been made in the development of an AOP from viral infection enhancement and virus production to thrombus formation. The contents of this abstract neither constitute nor necessarily reflect US EPA policy.
URLs/Downloads:
DOI: Increased susceptibility to viral entry and coronavirus production leading to thrombosis and disseminated intravascular coagulation: International joint research project for development of Adverse Outcome Pathway (AOP)
TANABE_SLIDESRS2021-9-2-21.PDF (PDF, NA pp, 4917.543 KB, about PDF)