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Plos Biology PLOS BIOLOGY RESEARCH ARTICLE A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19 Yadi Zhou1☯, Yuan Hou1☯, Jiayu Shen1, Reena Mehra2,3, Asha Kallianpur1,2, Daniel A. Culver4,5, Michaela U. Gack6, Samar Farha4,5, Joe Zein2,4, Suzy Comhair2,4, 2,4 2,4 2,4 1,2,4,7,8 Claudio Fiocchi , Thaddeus StappenbeckID , Timothy Chan , Charis EngID , Jae 2,4 2,3 2,4 1,2,8 a1111111111 U. Jung , Lara JehiID , Serpil Erzurum , Feixiong ChengID * a1111111111 a1111111111 1 Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America, 2 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western a1111111111 Reserve University, Cleveland, Ohio, United States of America, 3 Neurological Institute, Cleveland Clinic, a1111111111 Cleveland, Ohio, United States of America, 4 Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America, 5 Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, United States of America, 6 Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, Florida, United States of America, 7 Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America, 8 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, OPEN ACCESS United States of America Citation: Zhou Y, Hou Y, Shen J, Mehra R, Kallianpur A, Culver DA, et al. (2020) A network ☯ These authors contributed equally to this work. * [email protected] medicine approach to investigation and population- based validation of disease manifestations and drug repurposing for COVID-19. PLoS Biol 18(11): e3000970. https://doi.org/10.1371/journal. Abstract pbio.3000970 Academic Editor: Nicole Soranzo, Wellcome Trust The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respi- Sanger Institute, UNITED KINGDOM ratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and eco- Received: June 5, 2020 nomic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mecha- Accepted: October 28, 2020 nisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This Published: November 6, 2020 study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 Peer Review History: PLOS recognizes the therapies using network medicine methodologies along with clinical and multi-omics obser- benefits of transparency in the peer review vations. We incorporate SARS-CoV-2 virus±host protein±protein interactions, transcrip- process; therefore, we enable the publication of all of the content of peer review and author tomics, and proteomics into the human interactome. Network proximity measurement responses alongside final, published articles. The revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. editorial history of this article is available here: Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and https://doi.org/10.1371/journal.pbio.3000970 TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn dis- Copyright: © 2020 Zhou et al. This is an open ease patients compared to uninflamed tissues, revealing shared pathobiology between access article distributed under the terms of the COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and tran- Creative Commons Attribution License, which permits unrestricted use, distribution, and scriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares reproduction in any medium, provided the original an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). author and source are credited. To prioritize potential treatments, we combined network-based prediction and a propensity Data Availability Statement: All data sets used in score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. this study and their sources for downloading can We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56±0.91) is be found in S1 Table. The bulk and single-cell RNA- PLOS Biology | https://doi.org/10.1371/journal.pbio.3000970 November 6, 2020 1 / 43 PLOS BIOLOGY Network medicine for COVID-19 Seq data used in this study were downloaded from significantly associated with a 28% reduced likelihood of a positive laboratory test result for the NCBI GEO database with accession numbers SARS-CoV-2 confirmed by reverse transcription±polymerase chain reaction assay. Using a GSE63142, GSE130499, and GSE134809. The lung and human bronchial epithelial single-cell data PS matching user active comparator design, we determined that melatonin usage was asso- were downloaded from https://data.mendeley.com/ ciated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of datasets/7r2cwbw44m/1. Source code, the human angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54±0.92) or angiotensin-converting protein-protein interactome, and drug-target enzyme inhibitors (OR = 0.69, 95% CI 0.52±0.90). Importantly, melatonin usage (OR = network can be downloaded from https://github. com/ChengF-Lab/COVID-19_Map. All other 0.48, 95% CI 0.31±0.75) is associated with a 52% reduced likelihood of a positive laboratory relevant data are within the paper and its test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking Supporting Information files. history, and various disease comorbidities using PS matching. In summary, this study pres- Funding: This work was supported by the National ents an integrative network medicine platform for predicting disease manifestations associ- Institute of Aging (R01AG066707 and ated with COVID-19 and identifying melatonin for potential prevention and treatment of 3R01AG066707-01S1) and the National Heart, COVID-19. Lung, and Blood Institute (R00HL138272) to F.C. This work has been also supported in part by the VeloSano Pilot Program (Cleveland Clinic Taussig Cancer Institute) to F.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction Competing interests: The authors have declared The ongoing global coronavirus disease 2019 (COVID-19) pandemic has led to 38 million that no competing interests exist. confirmed cases and 1 million deaths worldwide as of October 14, 2020. The United States Abbreviations: ACEI, angiotensin-converting alone has recorded nearly 8 million confirmed cases, with a death toll of more than 216,000 enzyme inhibitor; AP-MS, affinity purification±mass [1]. Several retrospective studies have reported the clinical characteristics of individuals with spectrometry; ARB, angiotensin II receptor blocker; symptomatic COVID-19, and an emerging theme has been the significantly higher risk of AT2, alveolar type II; Co-IP+LC/MS, co- immunoprecipitation and liquid chromatography± morbidity and mortality among individuals with 1 or more comorbid health conditions, such mass spectrometry; COPD, chronic obstructive as hypertension, asthma, diabetes mellitus, cardiovascular or cerebrovascular disease, chronic pulmonary disease; COVID-19, coronavirus kidney disease, and malignancy [2±7]. However, these retrospective clinical studies are limited disease 2019; DEG, differentially expressed gene; by small sample sizes and unmeasured confounding factors, leaving the underlying patho- DEP, differentially expressed protein; dN/dS ratio, mechanisms largely unknown. More specifically, it is unclear whether associations of disease nonsynonymous to synonymous substitution rate ratio; ES, enrichment score; FDA, US Food and manifestations and COVID-19 severity are merely a reflection of poorer health in general, or a Drug Administration; FDR, false discovery rate; clue to shared pathobiological mechanisms. GSEA, gene set enrichment analysis; HCoV, human Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus; HGMD, Human Gene Mutation COVID-19, is an enveloped virus that carries a single-stranded positive-sense RNA genome Database; IBD, inflammatory bowel disease; KEGG, [7,8]. SARS-CoV-2 is a newly discovered member of the coronavirus (CoV) family [9]. SARS- Kyoto Encyclopedia of Genes and Genomes; OR, CoV-2 enters host cells via binding of its spike protein to the angiotensin converting enzyme 2 odds ratio; PPI, protein±protein interaction; PS, propensity score; RNA-Seq, RNA sequencing; (ACE2) receptor on the surfaces of many cell types [10]. This binding is primed by transmem- RNAi, RNA interference; SARS-CoV-2, severe acute brane protease serine 2 (TMPRSS2) [10] and the host cell protease furin [11] (Fig 1A). Studies respiratory syndrome coronavirus 2; viORF, viral have shown that ACE2 and TMPRSS2 are highly co-expressed in alveolar type II (AT2) epithe- open reading frame. lial cells in the lung [12], nasal mucosa [13], bronchial secretory cells [14], and absorptive enterocytes in the ileum [15]. Yet, much remains to be learned about how these critical human proteins involved in the infection and replication of SARS-CoV-2 are associated with various disease comorbidities and complications. Systematic identification of the host factors involved
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