key: cord-0824480-sekbogls authors: Vavougios, George D. title: Host – Virus – Drug interactions as determinants of COVID-19’s phenotypes: a data-driven hypothesis date: 2020-09-17 journal: Med Hypotheses DOI: 10.1016/j.mehy.2020.110275 sha: 4dd756d47da9b6deb3c45ed26278a932656f8dd7 doc_id: 824480 cord_uid: sekbogls There is a growing body of evidence on the significance of interactions between comorbidities, their treatments and COVID-19 clinical phenotypes. The hypothesis explored herein is that pharmaceutical compounds currently in use are affecting COVID-19 susceptibility and phenotypes by overlapping transcriptional networks. Using two distinct SARS-CoV-2 – host interactomes, gene set enrichment analysis is used to discover compounds and assorted gene signatures derived from SARS-CoV-2 interactomes. Micronutrients, antiplatelets, ACE2 inhibitors, NSAIDs, corticosteroids and tyrosine kinase inhibitors are among the compounds discovered. Considering the implication of their associated comorbidities such as diabetes and cardiovascular disease that are associated with severe COVID-19, this study outlines the need to consider specific compounds as modulators of the observed COVID-19 spectrum. Furthermore, given that micronutrient trafficking may be targeted by viral processes, and display synergism with other enriched compounds, such as statins, studies assessing their levels prior and during infection are more than warranted. and display synergism with other enriched compounds, such as statins, studies assessing their levels prior and during infection are more than warranted. There is a growing body of evidence on the significance of interactions between comorbidities and COVID-19 clinical phenotypes (1) . Correspondingly, observational studies that have attempted to link concomitant drugs with COVID-19 outcomes (2) . Recent advances in mapping the perturbations of SARS-CoV-2 infection on the host's transcriptome (3),(4) may allow a more in-depth approach, enabling the discovery of overlapping gene signatures at the host -drug -gene interface. The significance of these signatures lies in the potential modulation of COVID-19 outcomes, as well as determining the drug -modified host susceptibility prior to infection. The hypothesis explored herein is that pharmaceutical compounds currently in use are affecting transmission dynamics and COVID-19 phenotypes by host -virus -drug overlapping transcriptional networks. For the evaluation of this hypothesis, host -virus -drug interactions on the transcriptomic level were considered by interrogating a previously generated dataset (5) . For the generation of the host -virus -drug dataset, gene set enrichment analyses Following the reconstruction of the two interactomes, drug -gene set enrichment analyses (D-GSEA) were performed via the Enrichr web service (6), screening (a) the DSigDB, a database of human gene -drug interactions (7) and gene signatures extracted from drug perturbation experiments available on Gene Expression Omnibus (GEO) (8) . For all analyses, p-values and false discovery rates (FDR) <0.05 were considered statistically significant. Antihypertensives, NSAIDs, Corticosteroids, statins, specific kinase receptor inhibitors and anticoagulants were among salient drug classes significantly enriched by both SARS-CoV-2 gene signatures; Furthermore, trace metals and vitamins were also included in the list of significantly enriched compounds ( Table 1 and Supplementary Materials 1). Of note, valproic acid was associated with the largest gene signature, comprised of 157 genes from I A (Adjusted p-value=2.16e -7 ). The compounds identified via D-GSEA of host pathways affected by SARS-CoV-2 generally outline three major aspects of host -virus -drug interactions: (a) Host As a host factor, tissue micronutrient availability presents a major modifiable parameter affecting immune fitness. Several studies have shown that both trace metals and vitamins are implicated in maintaining crucial aspects of immunosurveillance and mounting an effective antiviral response (9) . Effective intracellular latency depends on the subversion of Cu and Zn trafficking from the host during the course of viral infections, with the efflux of these ions diverted to virion assembly and as cofactors to viral proteins (10), (11) . Aside from latency mechanisms, a perturbed intracellular copper trafficking axis furthermore amounts to impaired phagocytosis and thus susceptibility to pathogens requiring phagosomal copper repletion (12) . A deeper layer of interplay can be found in host -virus interactions on the transcriptional level (13) , (14) , as well as the conjugation of viral lifecycles, mutagenesis and their virulence with cellular micronutrient stores, as is the case with Cu (10) and Se (15) . Malnutrition as a substrate for the development of both severe COVID-19 and susceptibility to SARS-CoV-2 was among the earliest hypotheses in the literature (16). Currently, a recent study by Zhang and colleagues has indicated that Se nutritional status may be associated with COVID-19 outcomes (17) . Given selenium's role in platelet aggregation and endothelial interactions (18) , , its role in the development of severe disease manifestations such as coagulopathy (19) may account for these observations. ACEi are perhaps the most salient compounds governing this aspect of the host -virus -drug interactions. As ACE2 is indispensable for SARS-CoV-2's cellular entry (20) , ACEi are currently under evaluation as potential therapeutic compounds against . In a similar manner, statins have been previously evaluated in numerous RNA viruses as potential perturbators of lipid raft hijacking during the viral lifecycle (22). Considering the transcriptomic evidence supporting SARS-CoV-2's modulation of the host's metabolic cascades, it is likely that this strategy is also utilized by the novel coronavirus (23) . Notably, selenium supplementation and statins may function synergistically in downregulating HMG-CoA reductase (24) , indicating that micronutrient status may furthermore affect host-drug interactions aside from immune fitness. A major implication of this study's findings is that in the setting comorbidities associated with severe COVID-19 phenotypes, i.e. metabolic and cardiovascular disease, the risk may be mitigated by medications already received by these patients. In this sense, the potential host -virus -drug interactions should be considered both in risk stratification, but also in determining whether their cumulative effect results in positive outcomes. As a case in point, the risk of developing severe COVID-19 in patients receiving concomitant anticoagulant therapy may be mitigated between said anticoagulant use and concomitant cardiovascular comorbidities (25) , (26) . In the setting of COVID-19 phenotypic spectrum, it becomes evident that concomitant medication are already contributing to the observed outcomes. Aside from the detrimental effects of infection, comorbidities and the drugmodulated pathways of the host, the immune response and the effect of stress cascades may be contributing to what is perceived as severity and outcomes for COVID-19. The elevation of systemic stress and inflammation biomarkers indicates that the host's response may contribute to overall tissue and organ detriment (27) . Considering preliminary reports on the efficacy of dexamethasone in limiting mortality in severe COVID-19 (28) , agents limiting the host's stress and inflammatory responses may be correspondingly mitigating outcomes. Considering that dysregulated cytokine responses may emerge even from moderate disease stages and result in organ damage (29) , successful inflammation restriction whether host or host -drug mediated has been outlined a determinant of COVID-19's spectrum. In severe COVID-19, this niche would be addressed by empiric approaches such as NSAIDs, corticosteroids, glycemic control and secondary ischemic prevention measures (30) . In this study, the empirical approach is corroborated by transcriptomic evidence; specifically, pathways associated with the later compounds have already been targeted during the course of SARS-CoV-2's latency, and presumably function to precipitate each corresponding complication. In accordance to epidemiological observations, multiple gene signatures associated with significantly enriched compounds were identified by this study. These and population based studies. Given that regional nutritional status has previously been associated viral transmission dynamics (33) and disease severity (17) and the micronutrient associated gene signatures detected in this study, further scrutiny is necessary to determine their associations with relative to disease severity, outcomes, as well as their effect in combination with other compounds targeting the SARS-CoV-2host interface. Finally, less elucidated relationships those detected with valproate and benserazide may indicate that the emerging neuroinvasive potential of SARS-CoV-2 may too be modified by concomitant medication affecting the CNS, albeit towards currently unknown outcomes. The author declares that there is no real or perceived conflict of interest regarding the submitted manuscript. The order of selection was alphabetical, based on first author name. "Hits" refers to the number of genes comprising each drug -associated signature. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication Proteomics of SARS-CoV-2-infected host cells reveals therapy targets Master Regulator Analysis of the SARS-CoV-2/Human Interactome Selenium -associated gene signatures within the SARS-CoV-2 -host genomic interaction interface Enrichr: a comprehensive gene set enrichment analysis web server 2016 update DSigDB: drug signatures database for gene set analysis The Gene Expression Omnibus Database The Role of the Status of Selected Micronutrients in Shaping the Immune Function Host Cell Copper Transporters CTR1 and ATP7A are important for Influenza A virus replication The Role of Copper Homeostasis at the Host-Pathogen Axis: From Bacteria to Fungi The Role of Copper Homeostasis at the Host-Pathogen Axis: From Bacteria to Fungi Zinc-binding site of human immunodeficiency virus 2 Vpx prevents instability and dysfunction of the protein Selenium and vitamin E status: impact on viral pathogenicity Cellular Selenoprotein mRNA Tethering via Antisense Interactions with Ebola and HIV-1 mRNAs May Impact Host Selenium Biochemistry The Malnutritional Status of the Host as a Virulence Factor for New Coronavirus SARS-CoV-2 Association between regional selenium status and reported outcome of COVID-19 cases in China Effects of sodium selenite on in vitro interactions between platelets and endothelial cells Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19 Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Effects of Angiotensin II Receptor Blockers and ACE Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study Statins: a viable candidate for hostdirected therapy against infectious diseases A data-driven hypothesis on the epigenetic dysregulation of host metabolism by SARS coronaviral infection: Potential implications for the SARS-CoV-2 modus operandi Modulation of hypercholesterolemia-induced alterations in apolipoprotein B and HMG-CoA reductase expression by selenium supplementation Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action COVID-19 mortality in patients on anticoagulants and antiplatelet agents /bjh.16968Vargas-Vargas M, Cortes-Rojo C. Ferritin levels and COVID-19 COVID-19 treatment: close to a cure? A rapid review of pharmacotherapies for the novel coronavirus (SARS-CoV-2) Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts Pharmacotherapics Advice in Guidelines for COVID-19 Increased virulence of coxsackievirus B3 in mice due to vitamin E or selenium deficiency Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice The association between hantavirus infection and selenium deficiency in mainland China