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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology
Sarah Musa Hammoudeh, Arabella Musa Hammoudeh, Poorna Manasa Bhamidimarri, Bassam Mahboub, Rabih Halwani, Qutayba Hamid, Mohamed Rahmani, Rifat Hamoudi
Sarah Musa Hammoudeh, Poorna Manasa Bhamidimarri, Rabih Halwani, Qutayba Hamid, Mohamed Rahmani, Rifat Hamoudi, Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
Sarah Musa Hammoudeh, Arabella Musa Hammoudeh, Bassam Mahboub, Rabih Halwani, Qutayba Hamid, Mohamed Rahmani, Rifat Hamoudi, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
Arabella Musa Hammoudeh, General Surgery Department, Tawam Hospital, SEHA, Al-Ain 15258, United Arab Emirates
Bassam Mahboub, Rashid Hospital, 315 Umm Hurair Second, Dubai Health Authority, Dubai 4545, United Arab Emirates
Qutayba Hamid, Meakins-Christie Laboratories, McGill University, Quebec H4A 3J1, Montreal, Canada
Rifat Hamoudi, Division of Surgery and Interventional Science, University College London, London W1W 7TY, United Kingdom
Author contributions: Hammoudeh SM, Hammoudeh AM, Rahmani M, and Hamoudi R were responsible for the conception, design, and development of the methodology; Hammoudeh SM, Hammoudeh AM, Bhamidimarri PM, Rahmani M, and Hamoudi R were responsible for the application of the methodology, the bioinformatics analysis and data interpretation; Hammoudeh SM, Hammoudeh AM, Bhamidimarri PM, Mahboub B, Halwani R, Hamid Q, Rahmani M, and Hamoudi R were responsible for writing and reviewing the manuscript; Hamoudi R, Rahmani M, Hamid Q, and Halwani R were responsible for the supervision of the study; The final manuscript was approved by all authors.
Supported by The University of Sharjah, No. CoV19-0308, No. CoV19-0307 and No: 1901090254; Sharjah Research Academy, No: MED001; and Al-Jalila Foundation Seed Grant, No. AJF202019.
Institutional review board statement: The committee has granted an ethical approval for the above mentioned request and following documents.
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: All the transcriptomic data is shared in Gene Expression Omnibus with data sets GSE150316 and GSE112356. All other processed data are shared in the manuscript as tables or figures.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Rifat Hamoudi, PhD, Professor, Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, P.O. Box, Sharjah 27272, United Arab Emirates.
rhamoudi@sharjah.ac.ae
Received: February 6, 2021
Peer-review started: February 6, 2021
First decision: March 14, 2021
Revised: March 30, 2021
Accepted: May 10, 2021
Article in press: May 10, 2021
Published online: June 7, 2021
Processing time: 109 Days and 12.1 Hours
BACKGROUND
The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients.
AIM
To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction.
METHODS
The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR.
RESULTS
Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction.
CONCLUSION
Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.
Core Tip: Liver dysfunction was frequently observed in severe coronavirus disease 2019 (COVID-19) patients. However, the mechanism through which severe acute respiratory syndrome coronavirus 2 potentially elicits liver function abnormality is not fully understood. We report a thorough analysis of changes occurring at the gene expression level in liver tissue of severe COVID-19 patients. Our findings suggest that severe COVID-19 patients may have a lower hepatic detoxification capacity and may experience liver tissue remodeling resulting in liver dysfunction.
