{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T06:10:46Z","timestamp":1776319846030,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The SARS-CoV-2 virus\u2019s ability to induce hypercytokinemia and cause multiple organ failure makes it imperative to find effective treatments. To understand the mechanism of viral infection and its effects on organ tissues, we analyzed multiple single-cell and bulk RNAseq data from COVID-19 patients\u2019 organ samples. Various levels of severity of infection were accounted for, with comparative analyses between mild, moderate, and severely infected patients. Our analysis uncovered an upregulation of the innate immune response via several inflammatory genes, IL-2, IL-6, IL-8, IL-17A, and NF-\u03baB. Consequently, we found that the upregulation of these downstream effects can lead to organ injury. The downregulated pathways such as eukaryotic initiation factor 2 (eIF2) and eIF4-mediated host translation, were found to lead to an increased viral translation. We also found that the loss of inhibitory peptides can suppress an overactive innate immune response via NF-\u03baB and interleukin-mediated pathways. Investigation of viral-host protein mapping showed that the interaction of viral proteins with host proteins correlated with the down- and upregulation of host pathways such as decreased eIF2-mediated host translation and increased hypertrophy and fibrosis. Inflammation was increased via the stimulation of pro-inflammatory cytokines and suppression of host translation pathways that led to reduced inflammatory inhibitors. Cardiac hypertrophy and organ fibrosis were the results of increased inflammation in organs of severe and critical patients. Finally, we identified potential therapeutic targets for the treatment of COVID-19 and its deleterious effects on organs. Further experimental investigation would conclusively determine the effects of COVID-19 infection on organs other than the lungs and the effectiveness of the proposed therapeutic targets.<\/jats:p>","DOI":"10.3390\/v13122418","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T03:21:05Z","timestamp":1638847265000},"page":"2418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Single-Cell and Bulk RNASeq Profiling of COVID-19 Patients Reveal Immune and Inflammatory Mechanisms of Infection-Induced Organ Damage"],"prefix":"10.3390","volume":"13","author":[{"given":"Alexandrea","family":"Bass","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiran","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sivanesan","family":"Dakshanamurthy","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive Cancer Center, Molecular and Experimental Therapeutic Research in Oncology Program, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1126\/science.abc1669","article-title":"SARS-CoV-2 productively infects human gut enterocytes","volume":"369","author":"Lamers","year":"2020","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.cell.2020.04.004","article-title":"Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2","volume":"181","author":"Monteil","year":"2020","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40560-020-00453-4","article-title":"Lymphopenia in severe coronavirus disease-2019 (COVID-19): Systematic review and meta-analysis","volume":"8","author":"Huang","year":"2020","journal-title":"J. Intensive Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"108253","DOI":"10.1016\/j.exer.2020.108253","article-title":"Hypercytokinemia in COVID-19: Tear cytokine profile in hospitalized COVID-19 patients","volume":"200","author":"Santiago","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Matsuishi, Y., Mathis, B., Shimojo, N., Subrina, J., Okubo, N., and Inoue, Y. (2021). Severe COVID-19 Infection Associated with Endothelial Dysfunction Induces Multiple Organ Dysfunction: A Review of Therapeutic Interventions. Biomedicines, 9.","DOI":"10.3390\/biomedicines9030279"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1093\/nsr\/nwaa123","article-title":"Autopsy of COVID-19 patients in China","volume":"7","author":"Bian","year":"2020","journal-title":"Natl. Sci. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Thakur, V., Ratho, R., Kumar, P., Bhatia, S., Bora, I., Mohi, G., Saxena, S., Devi, M., Yadav, D., and Mehariya, S. (2021). Multi-Organ Involvement in COVID-19: Beyond Pulmonary Manifestations. J. Clin. Med., 10.","DOI":"10.3390\/jcm10030446"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1111\/liv.14470","article-title":"COVID-19 and liver disease","volume":"40","author":"Sun","year":"2020","journal-title":"Liver Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17720","DOI":"10.1038\/s41598-020-74666-w","article-title":"Multiple early introductions of SARS-CoV-2 into a global travel hub in the Middle East","volume":"10","author":"Tayoun","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"561264","DOI":"10.3389\/fpubh.2020.561264","article-title":"Clinical Symptom Differences Between Mild and Severe COVID-19 Patients in China: A Meta-Analysis","volume":"8","author":"He","year":"2021","journal-title":"Front. Public Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8896536","DOI":"10.1155\/2020\/8896536","article-title":"Metabolic Perturbations and Severe COVID-19 Disease: Implication of Molecular Pathways","volume":"2020","author":"Nigro","year":"2020","journal-title":"Int. J. Endocrinol."},{"key":"ref_12","first-page":"107","article-title":"COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets","volume":"595","author":"Delorey","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_13","unstructured":"Misharin, A., Lu, Z., Markov, N., and Wunderink, R. (2021, November 04). Single Cell RNA-Seq Analysis of Bronchial Epithelium in Patients with Severe SARS-CoV-2 Pneumonia, Available online: https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE168215."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6319","DOI":"10.1038\/s41467-020-20139-7","article-title":"Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection","volume":"11","author":"Desai","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.csbj.2020.12.016","article-title":"Host transcriptomic profiling of COVID-19 patients with mild, moderate, and severe clinical outcomes","volume":"19","author":"Jain","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/s41374-019-0329-3","article-title":"Interleukin-33 delays recovery of mucosal inflammation via downregulation of homeostatic ABCG5\/8 in the colon","volume":"100","author":"Mishima","year":"2020","journal-title":"Lab. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1007\/s13577-021-00484-5","article-title":"PI3K\/AKT signaling pathway: A possible target for adjuvant therapy in COVID-19","volume":"34","author":"Khezri","year":"2021","journal-title":"Hum. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"28738","DOI":"10.1074\/jbc.M112.375915","article-title":"Eukaryotic Initiation Factor 2 (eIF2) Signaling Regulates Proinflammatory Cytokine Expression and Bacterial Invasion","volume":"287","author":"Shrestha","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s12985-020-01362-6","article-title":"The role of host eIF2\u03b1 in viral infection","volume":"17","author":"Liu","year":"2020","journal-title":"Virol. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/etm.2020.9449","article-title":"Recombinant interleukin-2 stimulates lymphocyte recovery in patients with severe COVID-19","volume":"21","author":"Zhu","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"673","DOI":"10.2147\/JIR.S278335","article-title":"Inflammatory Cytokine: IL-17A Signaling Pathway in Patients Present with COVID-19 and Current Treatment Strategy","volume":"13","author":"Shibabaw","year":"2020","journal-title":"J. Inflamm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"ofaa153","DOI":"10.1093\/ofid\/ofaa153","article-title":"C-Reactive Protein Level May Predict the Risk of COVID-19 Aggravation","volume":"7","author":"Wang","year":"2020","journal-title":"Open Forum Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"602395","DOI":"10.3389\/fimmu.2020.602395","article-title":"Interleukin-8 as a Biomarker for Disease Prognosis of Coronavirus Disease-2019 Patients","volume":"11","author":"Li","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.4049\/jimmunol.1001829","article-title":"The Role of the Transcription Factor CREB in Immune Function","volume":"185","author":"Wen","year":"2010","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/s41420-020-00369-w","article-title":"SARS-CoV-2 infection: Can ferroptosis be a potential treatment target for multiple organ involvement?","volume":"6","author":"Yang","year":"2020","journal-title":"Cell Death Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1038\/s41598-021-81638-1","article-title":"Altered high-density lipoprotein composition and functions during severe COVID-19","volume":"11","author":"Begue","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_27","unstructured":"Marie-Laure, F., Roland, M., Johannes, Z., Minh-Ha, N., Marie, D., Louis, B., Laura, C., Marti, N.-P., Lauriane, L., and Beat, H.M. (2021). SARS-CoV-2 ORF7b: Is a bat virus protein homologue a major cause of COVID-19 symptoms?. bioRxiv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.yjmcc.2020.05.007","article-title":"p38 MAPK inhibition: A promising therapeutic approach for COVID-19","volume":"144","author":"Grimes","year":"2020","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"289","DOI":"10.2217\/imt-2020-0235","article-title":"An anti-CD6 antibody for the treatment of COVID-19 patients with cytokine-release syndrome: Report of three cases","volume":"13","author":"Filgueira","year":"2021","journal-title":"Immunotherapy"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Conca, W., Alabdely, M., Albaiz, F., Foster, M.W., Alamri, M., Alkaff, M., Al-Mohanna, F., Nagelkerke, N., and Almaghrabi, R.S. (2021). Serum \u03b22-microglobulin levels in Coronavirus disease 2019 (COVID-19): Another prognosticator of disease severity?. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0247758"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1080\/00325481.2020.1855921","article-title":"JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy","volume":"133","author":"Satarker","year":"2021","journal-title":"Postgrad. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Han, Y., Gao, S., Muegge, K., Zhang, W., and Zhou, B. (2015). Advanced Applications of RNA Sequencing and Challenges. Bioinform. Biol. Insights, 9s1.","DOI":"10.4137\/BBI.S28991"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/12\/2418\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:39:01Z","timestamp":1760168341000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/12\/2418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,2]]},"references-count":32,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["v13122418"],"URL":"https:\/\/doi.org\/10.3390\/v13122418","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,2]]}}}