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DOI: 10.1055/a-1886-2094
Pathway Analysis of Patients with Severe Acute Respiratory Syndrome

Abstract
Background Coronaviruses are emerging threats for human health, as demonstrated by the ongoing coronavirus disease 2019 (COVID-19) pandemic that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is closely related to SARS-CoV-1, which was the cause of the 2002–2004 SARS outbreak, but SARS-CoV-1 has been the subject of a relatively limited number of studies. Understanding the potential pathways and molecular targets of SARS-CoV-1 will contribute to current drug repurposing strategies by helping to predict potential drug-disease associations.
Methods A microarray dataset, GSE1739, of 10 SARS patients and 4 healthy controls was downloaded from NCBI’s GEO repository, and differential expression was identified using NCBI’s GEO2R software. Pathway and enrichment analysis of the differentially expressed genes was carried out using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis, respectively.
Results Our findings show that the drugs dexamethasone, filgrastim, interferon alfacon-1, and levodopa were among the most significant upstream regulators of differential gene expression in SARS patients, while neutrophil degranulation was the most significantly enriched pathway.
Conclusion An enhanced understanding of the pathways and molecular targets of SARS-CoV-1 in humans will contribute to current and future drug repurposing strategies, which are an essential tool to combat rapidly emerging health threats.
Publikationsverlauf
Eingereicht: 30. November 2021
Angenommen: 21. Juni 2022
Artikel online veröffentlicht:
11. August 2022
© 2022. Thieme. All rights reserved.
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Germany
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References
- 1 Liu DX, Liang JQ, Fung TS. Human Coronavirus-229E, -OC43, -NL63, and -HKU1 (Coronaviridae). In: Bamford DH, Zuckerman M, Hrsg. Encyclopedia of Virology (Fourth Edition). Oxford: Academic Press; 2021: 428-440
- 2 Kesheh MM, Hosseini P, Soltani S. et al. An overview on the seven pathogenic human coronaviruses. Reviews in Medical Virology 2022; 32: e2282
- 3 Ng YL, Salim CK, Chu JJH. Drug repurposing for COVID-19: Approaches, challenges and promising candidates. Pharmacol Ther 2021; 228: 107930
- 4 Venkatesan P. Repurposing drugs for treatment of COVID-19. The Lancet Respiratory Medicine 2021; 9: e63
- 5 Reghunathan R, Jayapal M, Hsu L-Y. et al. Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome. BMC Immunol 2005; 6: 2
- 6 Subramanian A, Tamayo P, Mootha VK. et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences 2005; 102: 15545-15550
- 7 Mootha VK, Lindgren CM, Eriksson K-F. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267-273
- 8 Hannigan GE, McDonald PC, Walsh MP. et al. Integrin-linked kinase: Not so ‘pseudo’ after all. Oncogene 2011; 30: 4375-4385
- 9 Brodehl A, Rezazadeh S, Williams T. et al. Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy. Transl Res 2019; 208: 15-29
- 10 Zheng C-C, Hu H-F, Hong P. et al. Significance of integrin-linked kinase (ILK) in tumorigenesis and its potential implication as a biomarker and therapeutic target for human cancer. Am J Cancer Res 2019; 9: 186-197
- 11 Bugler-Lamb AR, Hasib A, Weng X. et al. Adipocyte integrin-linked kinase plays a key role in the development of diet-induced adipose insulin resistance in male mice. Molecular Metabolism 2021; 49: 101197
- 12 Raman A, Reif GA, Dai Y. et al. Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease. JASN 2017; 28: 2708-2719
- 13 Pan L, North HA, Sahni V. et al. β1-Integrin and Integrin Linked Kinase Regulate Astrocytic Differentiation of Neural Stem Cells. PLOS ONE 2014; 9: e104335
- 14 Ahmed AU, Sarvestani ST, Gantier MP. et al. Integrin-linked Kinase Modulates Lipopolysaccharide- and Helicobacter pylori-induced Nuclear Factor κB-activated Tumor Necrosis Factor-α Production via Regulation of p65 Serine 536 Phosphorylation*. Journal of Biological Chemistry 2014; 289: 27776-27793
- 15 Hortelano S, López-Fontal R, Través PG. et al. ILK mediates LPS-induced vascular adhesion receptor expression and subsequent leucocyte trans-endothelial migration†. Cardiovascular Research 2010; 86: 283-292
- 16 Rahman M, Irmler M, Keshavan S. et al. Differential Effect of SARS-CoV-2 Spike Glycoprotein 1 on Human Bronchial and Alveolar Lung Mucosa Models: Implications for Pathogenicity. Viruses 2021; 13: 2537
- 17 Esfandiarei M, Suarez A, Amaral A. et al. Novel role for integrin-linked kinase in modulation of coxsackievirus B3 replication and virus-induced cardiomyocyte injury. Circ Res 2006; 99: 354-361
- 18 Tsai M-S, Chen S-H, Chang C-P. et al. Integrin-Linked Kinase Reduces H3K9 Trimethylation to Enhance Herpes Simplex Virus 1 Replication. Front Cell Infect Microbiol 2022; 12: 814307
- 19 Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives. Nature 2020; 582: 469-469
- 20 Maláska J, Stašek J, Duška F. et al. Effect of dexamethasone in patients with ARDS and COVID-19 (REMED trial) – study protocol for a prospective, multi-centre, open-label, parallel-group, randomized controlled trial. Trials 2022; 23: 35
- 21 Sinha S, Rosin NL, Arora R. et al. Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19. Nat Med 2022; 28: 201-211
- 22 Ghosh SS, Wang J, Yannie PJ. et al. Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development. J Endocr Soc 2020; 4 bvz039
- 23 Petruk G, Puthia M, Petrlova J. et al. SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity. J Mol Cell Biol 2020; 12: 916-932
- 24 Kruglikov IL, Scherer PE. Preexisting and inducible endotoxemia as crucial contributors to the severity of COVID-19 outcomes. PLOS Pathogens 2021; 17: e1009306
- 25 Price TH, Chatta GS, Dale DC. Effect of Recombinant Granulocyte Colony-Stimulating Factor on Neutrophil Kinetics in Normal Young and Elderly Humans. Blood 1996; 88: 335-340
- 26 Hemmat N, Derakhshani A, Bannazadeh Baghi H. et al. Neutrophils, Crucial, or Harmful Immune Cells Involved in Coronavirus Infection: A Bioinformatics Study. Frontiers in Genetics. 2020
- 27 Mousavi SR, Lotfi H, Salmanizadeh S. et al. An experimental in silico study on COVID-19: Response of neutrophil-related genes to antibiotics. Health. Sci Rep 2022; 5: e548
- 28 Ramesh P, Veerappapillai S, Karuppasamy R. Gene expression profiling of corona virus microarray datasets to identify crucial targets in COVID-19 patients. Gene Rep 2021; 22: 100980
- 29 Zhang AW, Morjaria S, Kaltsas A. et al. The Effect of Neutropenia and Filgrastim (G-CSF) on Cancer Patients With Coronavirus Disease 2019 (COVID-19) Infection. Clinical Infectious Diseases 2022; 74: 567-574
- 30 Melian EB, Plosker GL. Interferon Alfacon-1. Drugs 2001; 61: 1661-1691
- 31 Kumaki Y, Day CW, Wandersee MK. et al. Interferon alfacon 1 inhibits SARS-CoV infection in human bronchial epithelial Calu-3 cells. Biochemical and Biophysical Research Communications 2008; 371: 110-113
- 32 Loutfy MR, Blatt LM, Siminovitch KA. et al. Interferon Alfacon-1 Plus Corticosteroids in Severe Acute Respiratory SyndromeA Preliminary Study. JAMA 2003; 290: 3222-3228
- 33 Rao AR, Hidayathullah SM, Hegde K. et al. Parkinsonism: An emerging post COVID sequelae. IDCases 2022; 27: e01388
- 34 Li W-S, Chan L-L, Chao Y-X. et al. Parkinson’s disease following COVID-19: causal link or chance occurrence?. Journal of Translational Medicine 2020; 18: 493
- 35 Artusi CA, Romagnolo A, Ledda C. et al. COVID-19 and Parkinson’s Disease: What Do We Know So Far?. J Parkinsons Dis 2021; 11: 445-454
- 36 Giacalone VD, Margaroli C, Mall MA. et al. Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease. Int J Mol Sci 2020; 21: 851
- 37 Reusch N, De Domenico E, Bonaguro L. et al. Neutrophils in COVID-19. Frontiers in Immunology 2021; 652470