Next Article in Journal
MicroRNAs as Potential Biomarkers in Pituitary Adenomas
Next Article in Special Issue
Therapeutic Significance of microRNA-Mediated Regulation of PARP-1 in SARS-CoV-2 Infection
Previous Article in Journal
17β-Estradiol Regulates miR-9-5p and miR-9-3p Stability and Function in the Aged Female Rat Brain
Previous Article in Special Issue
microRNA Heterogeneity, Innate-Immune Defense and the Efficacy of SARS-CoV-2 Infection—A Commentary
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
ncRNA
Volume 7
Issue 3
10.3390/ncrna7030054
ncrna-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Non-Coding RNAs in COVID-19: Emerging Insights and Current Questions

by
Tobias Plowman
1,2 and
Dimitris Lagos
1,2,*
1
York Biomedical Research Institute, University of York, Wentworth Way, York YO10 5DD, UK
2
Hull York Medical School, University of York, Wentworth Way, York YO10 5DD, UK
*
Author to whom correspondence should be addressed.
Non-Coding RNA 2021, 7(3), 54; https://doi.org/10.3390/ncrna7030054
Submission received: 9 August 2021 / Revised: 28 August 2021 / Accepted: 29 August 2021 / Published: 31 August 2021
(This article belongs to the Collection Non-Coding RNAs, COVID-19, and Long-COVID)
Browse Figure
Review Reports Versions Notes

Abstract

:
The highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the causative agent of coronavirus disease 2019 (COVID-19) in late 2019, igniting an unprecedented pandemic. A mechanistic picture characterising the acute immunopathological disease in severe COVID-19 is develo**. Non-coding RNAs (ncRNAs) constitute the transcribed but un-translated portion of the genome and, until recent decades, have been undiscovered or overlooked. A growing body of research continues to demonstrate their interconnected involvement in the immune response to SARS-CoV-2 and COVID-19 development by regulating several of its pathological hallmarks: cytokine storm syndrome, haemostatic alterations, immune cell recruitment, and vascular dysregulation. There is also keen interest in exploring the possibility of host–virus RNA–RNA and RNA–RBP interactions. Here, we discuss and evaluate evidence demonstrating the involvement of short and long ncRNAs in COVID-19 and use this information to propose hypotheses for future mechanistic and clinical studies.

1. SARS-CoV-2 and COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most recently discovered human-infectious and pathogenic coronavirus (CoV) that is thought to have emerged in December 2019 in China [1,2]. It is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 is an enveloped positive-sense single-stranded RNA virus from the betacoronavirus subfamily and is approximately 80% identical in its nucleotide sequence to severe acute respiratory syndrome coronavirus (SARS-CoV) that caused a more short-lived pandemic in 2002–2003 [2]. Similar to SARS-CoV, SARS-CoV-2 binds the human angiotensin converting enzyme 2 (ACE2) receptor to gain host cell entry, focusing infection on respiratory cells [3], although other human ACE2-expressing cell types can be affected [4,5].
SARS-CoV-2 infection can lead to a wide range of outcomes from asymptomatic infection to life-threatening lung disease alongside peripheral disorders [3]. Severely affected patients present with acute respiratory distress syndrome (ARDS) from lung damage, thromboembolic disorders, cardiovascular, cardiac and gastro-intestinal dysregulation, and/or liver or kidney malfunction [6]. As a result, COVID-19 has a high mortality rate that is estimated to be around 1% of cases [7,8,9] and has the capacity to overwhelm healthcare systems if left to spread uncontained in a population. Mortality risk also increases sharply with associated risk factors, such as age, autoimmune conditions such as diabetes [10], and existing cardiovascular or chronic lung disease [11].

2. The Human Non-Coding Genome and COVID-19

The nuances in an organism’s genome were traditionally appreciated for the specific forms of proteins that it produced. According to this paradigm, a gene is transcribed to produce the corresponding RNA, and the translational machinery converts this nucleotide blueprint into an amino acid sequence with biological function, with differing sequences conferring altered functions that are helpful to the specific organism. However, transcribed RNA is not always translated, and it itself can have biological function without encoding protein, known as non-coding RNA (ncRNA).
Forms of ncRNA can be sub-classified based on length. Transcripts longer than 200 base pairs (bp) are deemed ‘long non-coding RNAs’ (lncRNAs), and those shorter than 200 bp are designated as small ncRNAs, such as microRNAs (miRNAs) or small nucleolar RNAs (snoRNAs). There further subdivisions exist, for instance lncRNAs encoded from intergenic regions are deemed lincRNA, and miRNAs with the 5′ and 3′ termini end joined together are called circular RNAs (circRNAs).
The non-coding portion in simple eukaryotes is between 25–50% of the genome; in plants and complex fungi, this number is generally between 50 and 75%, whilst in humans, an incredible 98.5% of the genome is non-coding [12]. Given that the majority of the mammalian genome is indeed transcribed [13], not only does this imply that ncRNAs may be key in facilitating the development of complex organisms, it may also relate to the ability of humans to produce multifaceted immune responses that are formulated from a cascade of integrated signalling events. Conversely, the genomically simpler parasitic by-products of the genetic code, viruses, also have the capacity to produce ncRNAs, utilising endogenous mechanisms to promote their propagation.
Until recent decades, the relevance of ncRNAs has been overlooked in biology. However, predictably, given their genomic prevalence, findings continue to demonstrate their involvement in key cellular processes. For instance, the lncRNA ** drug discovery, in disrupting RNA-RNA or RNA-protein interactions, to mitigate viral propagating mechanisms such as miRNA and RBP sponging, or to limit host hyperinflammation from viral ncRNA expression. COVID-19 may become endemic in years to come [104]; therefore, discovery of novel drug targets will be vital in improving disease outcomes. In this respect, unlocking the untapped potential of the non-coding transcriptome as a source of potentially druggable targets can be transformative in our search for COVID-19 therapeutics.
Altogether, the data presented herein and throughout the literature highlight a crucial role for ncRNAs in COVID-19. Further research is necessary to establish clinically usable miRNA signatures, to investigate ncRNA-based immunological and peripheral system regulation, to explore the importance of SARS-CoV-2 as a source of interacting RNA itself, and to uncover novel drug targets in this unprecedented disease.

Author Contributions

T.P. and D.L. wrote, edited, and reviewed the manuscript. Both authors have read and agreed to the published version of the manuscript.

Funding

COVID-19 research in the DL group and TP have been funded by the UKRI/MRC award to the UK Coronavirus Immunology Consortium (UK-CIC, MR/V028448/1).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank all colleagues contributing to COVID-19 research and the patients and their families for providing material for this research. The figure was generated in Biorender (biorender.com).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
  2. Zhou, P.; Yang, X.-L.; Wang, X.-G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L.; et al. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature 2020, 579, 270–273. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. V’kovski, P.; Kratzel, A.; Steiner, S.; Stalder, H.; Thiel, V. Coronavirus Biology and Replication: Implications for SARS-CoV-2. Nat. Rev. Microbiol. 2021, 19, 155–170. [Google Scholar] [CrossRef] [PubMed]
  4. Hamming, I.; Timens, W.; Bulthuis, M.; Lely, A.; Navis, G.; van Goor, H. Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis. J. Pathol. 2004, 203, 631–637. [Google Scholar] [CrossRef]
  5. Chen, L.; Li, X.; Chen, M.; Feng, Y.; **ong, C. The ACE2 Expression in Human Heart Indicates New Potential Mechanism of Heart Injury among Patients Infected with SARS-CoV-2. Cardiovasc. Res. 2020, 116, 1097–1100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Shanmugam, C.; Mohammed, A.R.; Ravuri, S.; Luthra, V.; Rajagopal, N.; Karre, S. COVID-2019—A Comprehensive Pathology Insight. Pathol. Res. Pract. 2020, 216, 153222. [Google Scholar] [CrossRef] [PubMed]
  7. Petersen, E.; Koopmans, M.; Go, U.; Hamer, D.H.; Petrosillo, N.; Castelli, F.; Storgaard, M.; Al Khalili, S.; Simonsen, L. Comparing SARS-CoV-2 with SARS-CoV and Influenza Pandemics. Lancet Infect. Dis. 2020, 20, e238–e244. [Google Scholar] [CrossRef]
  8. Wu, J.T.; Leung, K.; Bushman, M.; Kishore, N.; Niehus, R.; de Salazar, P.M.; Cowling, B.J.; Lipsitch, M.; Leung, G.M. Estimating Clinical Severity of COVID-19 from the Transmission Dynamics in Wuhan, China. Nat. Med. 2020, 26, 506–510. [Google Scholar] [CrossRef] [Green Version]
  9. Ferguson, N.; Laydon, D.; Nedjati Gilani, G.; Imai, N.; Ainslie, K.; Baguelin, M.; Bhatia, S.; Boonyasiri, A.; Cucunuba Perez, Z.; Cuomo-Dannenburg, G.; et al. Report 9: Impact of Non-Pharmaceutical Interventions (NPIs) to Reduce COVID19 Mortality and Healthcare Demand; Imperial College: London, UK, 2020. [Google Scholar]
  10. Holman, N.; Knighton, P.; Kar, P.; O’Keefe, J.; Curley, M.; Weaver, A.; Barron, E.; Bakhai, C.; Khunti, K.; Wareham, N.J.; et al. Risk Factors for COVID-19-Related Mortality in People with Type 1 and Type 2 Diabetes in England: A Population-Based Cohort Study. Lancet Diabetes Endocrinol. 2020, 8, 823–833. [Google Scholar] [CrossRef]
  11. Jordan, R.E.; Adab, P.; Cheng, K.K. Covid-19: Risk Factors for Severe Disease and Death. BMJ 2020, 368, m1198. [Google Scholar] [CrossRef] [Green Version]
  12. Mattick, J.S. RNA Regulation: A New Genetics? Nat. Rev. Genet. 2004, 5, 316–323. [Google Scholar] [CrossRef]
  13. The FANTOM Consortium. The Transcriptional Landscape of the Mammalian Genome. Science 2005, 309, 1559–1563. [Google Scholar] [CrossRef] [Green Version]
  14. Brockdorff, N.; Ashworth, A.; Kay, G.F.; McCabe, V.M.; Norris, D.P.; Cooper, P.J.; Swift, S.; Rastan, S. The Product of the Mouse **st Gene Is a 15 Kb Inactive X-Specific Transcript Containing No Conserved ORF and Located in the Nucleus. Cell 1992, 71, 515–526. [Google Scholar] [CrossRef]
  15. Ridings-Figueroa, R.; Stewart, E.R.; Nesterova, T.B.; Coker, H.; Pintacuda, G.; Godwin, J.; Wilson, R.; Haslam, A.; Lilley, F.; Ruigrok, R.; et al. The Nuclear Matrix Protein CIZ1 Facilitates Localization of **st RNA to the Inactive X-Chromosome Territory. Genes Dev. 2017, 31, 876–888. [Google Scholar] [CrossRef] [Green Version]
  16. Zhang, B.; Arun, G.; Mao, Y.S.; Lazar, Z.; Hung, G.; Bhattacharjee, G.; **ao, X.; Booth, C.J.; Wu, J.; Zhang, C.; et al. The LncRNA Malat1 Is Dispensable for Mouse Development but Its Transcription Plays a Cis-Regulatory Role in the Adult. Cell Rep. 2012, 2, 111–123. [Google Scholar] [CrossRef] [Green Version]
  17. Hewitson, J.P.; West, K.A.; James, K.R.; Rani, G.F.; Dey, N.; Romano, A.; Brown, N.; Teichmann, S.A.; Kaye, P.M.; Lagos, D. Malat1 Suppresses Immunity to Infection through Promoting Expression of Maf and IL-10 in Th Cells. J. Immunol. 2020, 204, 2949–2960. [Google Scholar] [CrossRef] [Green Version]
  18. Shimakami, T.; Yamane, D.; Jangra, R.K.; Kempf, B.J.; Spaniel, C.; Barton, D.J.; Lemon, S.M. Stabilization of Hepatitis C Virus RNA by an Ago2-MiR-122 Complex. Proc. Natl. Acad. Sci. USA 2012, 109, 941–946. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Farr, R.J.; Rootes, C.L.; Rowntree, L.C.; Nguyen, T.H.O.; Hensen, L.; Kedzierski, L.; Cheng, A.C.; Kedzierska, K.; Au, G.G.; Marsh, G.A.; et al. Altered MicroRNA Expression in COVID-19 Patients Enables Identification of SARS-CoV-2 Infection. PLoS Pathog. 2021, 17, e1009759. [Google Scholar] [CrossRef] [PubMed]
  20. Kaneko, A. Tocilizumab in Rheumatoid Arthritis: Efficacy, Safety and Its Place in Therapy. Ther. Adv. Chronic Dis. 2013, 4, 15–21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Hayakawa, K.; Kawasaki, M.; Hirai, T.; Yoshida, Y.; Tsushima, H.; Fujishiro, M.; Ikeda, K.; Morimoto, S.; Takamori, K.; Sekigawa, I. MicroRNA-766-3p Contributes to Anti-Inflammatory Responses through the Indirect Inhibition of NF-ΚB Signaling. IJMS 2019, 20, 809. [Google Scholar] [CrossRef] [Green Version]
  22. Xu, N.; Meisgen, F.; Butler, L.M.; Han, G.; Wang, X.-J.; Söderberg-Nauclér, C.; Ståhle, M.; Pivarcsi, A.; Sonkoly, E. MicroRNA-31 is Overexpressed in Psoriasis and Modulates Inflammatory Cytokine and Chemokine Production in Keratinocytes via Targeting Serine/Threonine Kinase 40. J. Immunol. 2013, 190, 678–688. [Google Scholar] [CrossRef] [Green Version]
  23. Mi, B.; Li, Q.; Li, T.; Liu, G.; Sai, J. High MiR-31-5p Expression Promotes Colon Adenocarcinoma Progression by Targeting TNS1. Aging 2020, 12, 7480–7490. [Google Scholar] [CrossRef]
  24. Tian, Y.; Xu, J.; Li, Y.; Zhao, R.; Du, S.; Lv, C.; Wu, W.; Liu, R.; Sheng, X.; Song, Y.; et al. MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice. Gastroenterology 2019, 156, 2281–2296.e6. [Google Scholar] [CrossRef]
  25. Sabbatinelli, J.; Giuliani, A.; Matacchione, G.; Latini, S.; Laprovitera, N.; Pomponio, G.; Ferrarini, A.; Svegliati Baroni, S.; Pavani, M.; Moretti, M.; et al. Decreased Serum Levels of the Inflammaging Marker MiR-146a Are Associated with Clinical Non-Response to Tocilizumab in COVID-19 Patients. Mech. Ageing Dev. 2021, 193, 111413. [Google Scholar] [CrossRef] [PubMed]
  26. Ye, E.-A.; Steinle, J.J. MiR-146a Suppresses STAT3/VEGF Pathways and Reduces Apoptosis through IL-6 Signaling in Primary Human Retinal Microvascular Endothelial Cells in High Glucose Conditions. Vis. Res. 2017, 139, 15–22. [Google Scholar] [CrossRef]
  27. Jiang, S.; Hu, Y.; Deng, S.; Deng, J.; Yu, X.; Huang, G.; Kawai, T.; Han, X. MiR-146a Regulates Inflammatory Cytokine Production in Porphyromonas Gingivalis Lipopolysaccharide-Stimulated B Cells by Targeting IRAK1 but Not TRAF6. Biochim. Biophys. Acta (BBA)—Mol. Basis Dis. 2018, 1864, 925–933. [Google Scholar] [CrossRef]
  28. Moazzam-Jazi, M.; Lanjanian, H.; Maleknia, S.; Hedayati, M.; Daneshpour, M.S. Interplay between SARS-CoV-2 and Human Long Non-coding RNAs. J. Cell Mol. Med. 2021, 25, 5823–5827. [Google Scholar] [CrossRef]
  29. Iacona, J.R.; Lutz, C.S. MiR-146a-5p: Expression, Regulation, and Functions in Cancer. WIREs RNA 2019, e1533. [Google Scholar] [CrossRef]
  30. Miao, C.; Bai, L.; Yang, Y.; Huang, J. Dysregulation of LncRNAs in Rheumatoid Arthritis: Biomarkers, Pathogenesis and Potential Therapeutic Targets. Front. Pharmacol. 2021, 12, 652751. [Google Scholar] [CrossRef]
  31. Vishnubalaji, R.; Shaath, H.; Alajez, N.M. Protein Coding and Long Noncoding RNA (LncRNA) Transcriptional Landscape in SARS-CoV-2 Infected Bronchial Epithelial Cells Highlight a Role for Interferon and Inflammatory Response. Genes 2020, 11, 760. [Google Scholar] [CrossRef]
  32. Wei, L.; Li, J.; Han, Z.; Chen, Z.; Zhang, Q. Silencing of LncRNA MALAT1 Prevents Inflammatory Injury after Lung Transplant Ischemia-Reperfusion by Downregulation of IL-8 via P300. Mol. Ther. Nucleic Acids 2019, 18, 285–297. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Huang, K.; Wang, C.; Vagts, C.; Raguveer, V.; Finn, P.W.; Perkins, D.L. Long Non-Coding RNAs (LncRNAs) NEAT1 and MALAT1 Are Differentially Expressed in Severe COVID-19 Patients: An Integrated Single Cell Analysis. medRxiv 2021. [Google Scholar] [CrossRef]
  34. Cui, H.; Banerjee, S.; Guo, S.; **e, N.; Ge, J.; Jiang, D.; Zörnig, M.; Thannickal, V.J.; Liu, G. Long Noncoding RNA Malat1 Regulates Differential Activation of Macrophages and Response to Lung Injury. JCI Insight 2019, 4, e124522. [Google Scholar] [CrossRef] [Green Version]
  35. Masoumi, F.; Ghorbani, S.; Talebi, F.; Branton, W.G.; Rajaei, S.; Power, C.; Noorbakhsh, F. Malat1 Long Noncoding RNA Regulates Inflammation and Leukocyte Differentiation in Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2019, 328, 50–59. [Google Scholar] [CrossRef]
  36. Zhang, P.; Cao, L.; Zhou, R.; Yang, X.; Wu, M. The LncRNA Neat1 Promotes Activation of Inflammasomes in Macrophages. Nat. Commun. 2019, 10, 1495. [Google Scholar] [CrossRef] [Green Version]
  37. Centa, A.; Fonseca, A.S.; da Silva Ferreira, S.G.; Azevedo, M.L.V.; de Paula, C.B.V.; Nagashima, S.; Machado-Souza, C.; dos Santos Miggiolaro, A.F.R.; Pellegrino Baena, C.; de Noronha, L.; et al. Deregulated MiRNA Expression Is Associated with Endothelial Dysfunction in Post-Mortem Lung Biopsies of COVID-19 Patients. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2021, 320, L405–L412. [Google Scholar] [CrossRef] [PubMed]
  38. Li, H.; Yang, T.; Fei, Z. MiR-26a-5p Alleviates Lipopolysaccharide-induced Acute Lung Injury by Targeting the Connective Tissue Growth Factor. Mol. Med. Rep. 2020, 23. [Google Scholar] [CrossRef]
  39. Yue, X.-G.; Li, S.-J.; Zhang, Y.; Yang, Z.-G.; Li, H. Regulation of Diabetes-Induced Inflammation in Macrophages by MicroRNA-26a-5p. Int. J. Clin. Exp. Pathol. 2016, 9, 10074–10079. [Google Scholar]
  40. Li, Z.; Yi, N.; Chen, R.; Meng, Y.; Wang, Y.; Liu, H.; Cao, W.; Hu, Y.; Gu, Y.; Tong, C.; et al. MiR-29b-3p Protects Cardiomyocytes against Endotoxin-Induced Apoptosis and Inflammatory Response through Targeting FOXO3A. Cell. Signal. 2020, 74, 109716. [Google Scholar] [CrossRef]
  41. Wang, J.; Zhu, M.; Ye, L.; Chen, C.; She, J.; Song, Y. MiR-29b-3p Promotes Particulate Matter-Induced Inflammatory Responses by Regulating the C1QTNF6/AMPK Pathway. Aging 2020, 12, 1141–1158. [Google Scholar] [CrossRef]
  42. Gambardella, J.; Sardu, C.; Morelli, M.B.; Messina, V.; Marfella, R.; Maggi, P.; Paolisso, G.; Wang, X.; Santulli, G. Abstract 221: Exosomal MicroRNAs Drive Tromboembolism in Covid-19. Circulation 2020, 142, A221. [Google Scholar] [CrossRef]
  43. Sun, S.; Chai, S.; Zhang, F.; Lu, L. Overexpressed MicroRNA-103a-3p Inhibits Acute Lower-extremity Deep Venous Thrombosis via Inhibition of CXCL12. IUBMB Life 2020, 72, 492–504. [Google Scholar] [CrossRef] [PubMed]
  44. Hsu, Y.-L.; Hung, J.-Y.; Chang, W.-A.; Jian, S.-F.; Lin, Y.-S.; Pan, Y.-C.; Wu, C.-Y.; Kuo, P.-L. Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN. Mol. Ther. 2018, 26, 568–581. [Google Scholar] [CrossRef] [Green Version]
  45. Sahu, A.; Jha, P.K.; Prabhakar, A.; Singh, H.D.; Gupta, N.; Chatterjee, T.; Tyagi, T.; Sharma, S.; Kumari, B.; Singh, S.; et al. MicroRNA-145 Impedes Thrombus Formation via Targeting Tissue Factor in Venous Thrombosis. EBioMedicine 2017, 26, 175–186. [Google Scholar] [CrossRef] [Green Version]
  46. Grover, S.P.; Mackman, N. Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis. ATVB 2018, 38, 709–725. [Google Scholar] [CrossRef] [Green Version]
  47. Zhang, T.; Guo, J.; Gu, J.; Wang, Z.; Wang, G.; Li, H.; Wang, J. Identifying the Key Genes and MicroRNAs in Colorectal Cancer Liver Metastasis by Bioinformatics Analysis and In vitro Experiments. Oncol. Rep. 2018, 41, 279–291. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Delrue, M.; Siguret, V.; Neuwirth, M.; Joly, B.; Beranger, N.; Sène, D.; Chousterman, B.G.; Voicu, S.; Bonnin, P.; Mégarbane, B.; et al. Von Willebrand Factor/ADAMTS13 Axis and Venous Thromboembolism in Moderate-to-severe COVID-19 Patients. Br. J. Haematol. 2021, 192, 1097–1100. [Google Scholar] [CrossRef] [PubMed]
  49. Wang, X.; Sundquist, K.; Elf, J.L.; Strandberg, K.; Svensson, P.J.; Hedelius, A.; Palmér, K.; Memon, A.A.; Sundquist, J.; Zöller, B. Diagnostic Potential of Plasma MicroRNA Signatures in Patients with Deep-Vein Thrombosis. Thromb. Haemost. 2016, 116, 328–336. [Google Scholar] [CrossRef] [PubMed]
  50. Starikova, I.; Jamaly, S.; Sorrentino, A.; Blondal, T.; Latysheva, N.; Sovershaev, M.; Hansen, J.-B. Differential Expression of Plasma MiRNAs in Patients with Unprovoked Venous Thromboembolism and Healthy Control Individuals. Thromb. Res. 2015, 136, 566–572. [Google Scholar] [CrossRef]
  51. Forrest, A.R.R.; Kanamori-Katayama, M.; Tomaru, Y.; Lassmann, T.; Ninomiya, N.; Takahashi, Y.; de Hoon, M.J.L.; Kubosaki, A.; Kaiho, A.; Suzuki, M.; et al. Induction of MicroRNAs, Mir-155, Mir-222, Mir-424 and Mir-503, Promotes Monocytic Differentiation through Combinatorial Regulation. Leukemia 2010, 24, 460–466. [Google Scholar] [CrossRef] [Green Version]
  52. Garg, A.; Seeliger, B.; Derda, A.A.; **ao, K.; Gietz, A.; Scherf, K.; Sonnenschein, K.; Pink, I.; Hoeper, M.M.; Welte, T.; et al. Circulating Cardiovascular microRNAs in Critically Ill COVID-19 Patients. Eur. J. Heart Fail. 2021, 23, 468–475. [Google Scholar] [CrossRef] [PubMed]
  53. Cheng, Y.; Ji, R.; Yue, J.; Yang, J.; Liu, X.; Chen, H.; Dean, D.B.; Zhang, C. MicroRNAs Are Aberrantly Expressed in Hypertrophic Heart. Am. J. Pathol. 2007, 170, 1831–1840. [Google Scholar] [CrossRef] [Green Version]
  54. Thum, T.; Gross, C.; Fiedler, J.; Fischer, T.; Kissler, S.; Bussen, M.; Galuppo, P.; Just, S.; Rottbauer, W.; Frantz, S.; et al. MicroRNA-21 Contributes to Myocardial Disease by Stimulating MAP Kinase Signalling in Fibroblasts. Nature 2008, 456, 980–984. [Google Scholar] [CrossRef]
  55. Sayed, D.; He, M.; Hong, C.; Gao, S.; Rane, S.; Yang, Z.; Abdellatif, M. MicroRNA-21 Is a Downstream Effector of AKT That Mediates Its Antiapoptotic Effects via Suppression of Fas Ligand. J. Biol. Chem. 2010, 285, 20281–20290. [Google Scholar] [CrossRef] [Green Version]
  56. Mahesh, G.; Biswas, R. MicroRNA-155: A Master Regulator of Inflammation. J. Interferon Cytokine Res. 2019, 39, 321–330. [Google Scholar] [CrossRef]
  57. Van Rooij, E.; Quiat, D.; Johnson, B.A.; Sutherland, L.B.; Qi, X.; Richardson, J.A.; Kelm, R.J.; Olson, E.N. A Family of MicroRNAs Encoded by Myosin Genes Governs Myosin Expression and Muscle Performance. Dev. Cell 2009, 17, 662–673. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Van Rooij, E.; Sutherland, L.B.; Qi, X.; Richardson, J.A.; Hill, J.; Olson, E.N. Control of Stress-Dependent Cardiac Growth and Gene Expression by a MicroRNA. Science 2007, 316, 575–579. [Google Scholar] [CrossRef] [Green Version]
  59. Henderson, L.A.; Canna, S.W.; Schulert, G.S.; Volpi, S.; Lee, P.Y.; Kernan, K.F.; Caricchio, R.; Mahmud, S.; Hazen, M.M.; Halyabar, O.; et al. On the Alert for Cytokine Storm: Immunopathology in COVID-19. Arthritis Rheumatol. 2020, 72, 1059–1063. [Google Scholar] [CrossRef] [Green Version]
  60. Ragab, D.; Salah Eldin, H.; Taeimah, M.; Khattab, R.; Salem, R. The COVID-19 Cytokine Storm; What We Know So Far. Front. Immunol. 2020, 11, 1446. [Google Scholar] [CrossRef] [PubMed]
  61. Ruan, Q.; Yang, K.; Wang, W.; Jiang, L.; Song, J. Clinical Predictors of Mortality Due to COVID-19 Based on an Analysis of Data of 150 Patients from Wuhan, China. Intensive Care Med. 2020, 46, 846–848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Campochiaro, C.; Dagna, L. The Conundrum of Interleukin-6 Blockade in COVID-19. Lancet Rheumatol. 2020, 2, e579–e580. [Google Scholar] [CrossRef]
  63. Thwaites, R.S.; Sanchez Sevilla Uruchurtu, A.; Siggins, M.K.; Liew, F.; Russell, C.D.; Moore, S.C.; Fairfield, C.; Carter, E.; Abrams, S.; Short, C.-E.; et al. Inflammatory Profiles across the Spectrum of Disease Reveal a Distinct Role for GM-CSF in Severe COVID-19. Sci. Immunol. 2021, 6, eabg9873. [Google Scholar] [CrossRef] [PubMed]
  64. Henter, J.-I.; Horne, A.; Aricó, M.; Egeler, R.M.; Filipovich, A.H.; Imashuku, S.; Ladisch, S.; McClain, K.; Webb, D.; Winiarski, J.; et al. HLH-2004: Diagnostic and Therapeutic Guidelines for Hemophagocytic Lymphohistiocytosis. Pediatr. Blood Cancer 2007, 48, 124–131. [Google Scholar] [CrossRef] [PubMed]
  65. Dufranc, E.; Del Bello, A.; Belliere, J.; Kamar, N.; Faguer, S.; On Behalf of the TAIDI (Toulouse Acquired Immune Deficiency and Infection) Study Group. IL6-R Blocking with Tocilizumab in Critically Ill Patients with Hemophagocytic Syndrome. Crit. Care 2020, 24, 166. [Google Scholar] [CrossRef] [Green Version]
  66. Zhou, Y.-F.; Fu, Z.-Y.; Chen, X.-H.; Cui, Y.; Ji, C.-B.; Guo, X.-R. Tumor Necrosis Factor-α and Interleukin-6 Suppress MicroRNA-1275 Transcription in Human Adipocytes through Nuclear Factor-ΚB. Mol. Med. Rep. 2017, 16, 5965–5971. [Google Scholar] [CrossRef] [Green Version]
  67. The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with COVID-19. N. Engl. J. Med. 2021, 384, 693–704. [Google Scholar] [CrossRef]
  68. Abani, O.; Abbas, A.; Abbas, F.; Abbas, M.; Abbasi, S.; Abbass, H.; Abbott, A.; Abdallah, N.; Abdelaziz, A.; Abdelfattah, M.; et al. Tocilizumab in Patients Admitted to Hospital with COVID-19 (RECOVERY): A Randomised, Controlled, Open-Label, Platform Trial. Lancet 2021, 397, 1637–1645. [Google Scholar] [CrossRef]
  69. Sun, H.; Guo, P.; Zhang, L.; Wang, F. Serum Interleukin-6 Concentrations and the Severity of COVID-19 Pneumonia: A Retrospective Study at a Single Center in Bengbu City, Anhui Province, China, in January and February 2020. Med. Sci. Monit. 2020, 26. [Google Scholar] [CrossRef]
  70. Wang, D.; Xu, X. A Multicenter, Randomized Controlled Trial for the Efficacy and Safety of Tocilizumab in the Treatment of New Coronavirus Pneumonia (COVID-19); Chinese Clinical Trial Registry. 2020. Available online: www.chictr.org.cn/showprojen.aspx?proj=49409 (accessed on 9 August 2021).
  71. Salama, C.; Han, J.; Yau, L.; Reiss, W.G.; Kramer, B.; Neidhart, J.D.; Criner, G.J.; Kaplan-Lewis, E.; Baden, R.; Pandit, L.; et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N. Engl. J. Med. 2021, 384, 20–30. [Google Scholar] [CrossRef]
  72. Luly, F.R.; Lévêque, M.; Licursi, V.; Cimino, G.; Martin-Chouly, C.; Théret, N.; Negri, R.; Cavinato, L.; Ascenzioni, F.; Del Porto, P. MiR-146a Is over-Expressed and Controls IL-6 Production in Cystic Fibrosis Macrophages. Sci. Rep. 2019, 9, 16259. [Google Scholar] [CrossRef] [Green Version]
  73. Pan, J.; Du, M.; Cao, Z.; Zhang, C.; Hao, Y.; Zhu, J.; He, H. MiR-146a-5p Attenuates IL-1β-induced IL-6 and IL-1β Expression in a Cementoblast-derived Cell Line. Oral Dis. 2020, 26, 1308–1317. [Google Scholar] [CrossRef]
  74. Boldin, M.P.; Taganov, K.D.; Rao, D.S.; Yang, L.; Zhao, J.L.; Kalwani, M.; Garcia-Flores, Y.; Luong, M.; Devrekanli, A.; Xu, J.; et al. MiR-146a Is a Significant Brake on Autoimmunity, Myeloproliferation, and Cancer in Mice. J. Exp. Med. 2011, 208, 1189–1201. [Google Scholar] [CrossRef]
  75. Liu, G.; Park, Y.-J.; Abraham, E. Interleukin-1 Receptor-associated Kinase (IRAK) -1- Mediated NF-κ Activation Requires Cytosolic and Nuclear Activity. FASEB J. 2008, 22, 2285–2296. [Google Scholar] [CrossRef]
  76. Saulle, I.; Garziano, M.; Fenizia, C.; Cappelletti, G.; Parisi, F.; Clerici, M.; Cetin, I.; Savasi, V.; Biasin, M. MiRNA Profiling in Plasma and Placenta of SARS-CoV-2-Infected Pregnant Women. Cells 2021, 10, 1788. [Google Scholar] [CrossRef]
  77. Mann, M.; Mehta, A.; Zhao, J.L.; Lee, K.; Marinov, G.K.; Garcia-Flores, Y.; Lu, L.-F.; Rudensky, A.Y.; Baltimore, D. An NF-ΚB-MicroRNA Regulatory Network Tunes Macrophage Inflammatory Responses. Nat. Commun. 2017, 8, 851. [Google Scholar] [CrossRef] [Green Version]
  78. Tomazini, B.M.; Maia, I.S.; Cavalcanti, A.B.; Berwanger, O.; Rosa, R.G.; Veiga, V.C.; Avezum, A.; Lopes, R.D.; Bueno, F.R.; Silva, M.V.A.O.; et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients with Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA 2020, 324, 1307. [Google Scholar] [CrossRef]
  79. Zheng, Y.; **ong, S.; Jiang, P.; Liu, R.; Liu, X.; Qian, J.; Zheng, X.; Chu, Y. Glucocorticoids Inhibit Lipopolysaccharide-Mediated Inflammatory Response by Downregulating MicroRNA-155: A Novel Anti-Inflammation Mechanism. Free. Radic. Biol. Med. 2012, 52, 1307–1317. [Google Scholar] [CrossRef]
  80. Li, X.; Liu, C.; Mao, Z.; **ao, M.; Wang, L.; Qi, S.; Zhou, F. Predictive Values of Neutrophil-to-Lymphocyte Ratio on Disease Severity and Mortality in COVID-19 Patients: A Systematic Review and Meta-Analysis. Crit. Care 2020, 24, 647. [Google Scholar] [CrossRef] [PubMed]
  81. Liao, M.; Liu, Y.; Yuan, J.; Wen, Y.; Xu, G.; Zhao, J.; Cheng, L.; Li, J.; Wang, X.; Wang, F.; et al. Single-Cell Landscape of Bronchoalveolar Immune Cells in Patients with COVID-19. Nat. Med. 2020, 26, 842–844. [Google Scholar] [CrossRef] [PubMed]
  82. Wang, J.; Li, Q.; Yin, Y.; Zhang, Y.; Cao, Y.; Lin, X.; Huang, L.; Hoffmann, D.; Lu, M.; Qiu, Y. Excessive Neutrophils and Neutrophil Extracellular Traps in COVID-19. Front. Immunol. 2020, 11, 2063. [Google Scholar] [CrossRef] [PubMed]
  83. Toraih, E.A.; Sedhom, J.A.; Dokunmu, T.M.; Hussein, M.H.; Ruiz, E.M.L.; Muthusamy, K.; Zerfaoui, M.; Kandil, E. Hidden in Plain Sight: The Effects of BCG Vaccination in the COVID-19 Pandemic. J. Med. Virol. 2021, 93, 1950–1966. [Google Scholar] [CrossRef]
  84. Wu, Y.; Zhao, T.; Deng, R.; **a, X.; Li, B.; Wang, X. A Study of Differential CircRNA and LncRNA Expressions in COVID-19-Infected Peripheral Blood. Sci. Rep. 2021, 11, 7991. [Google Scholar] [CrossRef]
  85. Hyers, T.M. Venous Thromboembolism. Am. J. Respir. Crit. Care Med. 1999, 159, 1–14. [Google Scholar] [CrossRef]
  86. Tan, B.K.; Mainbourg, S.; Friggeri, A.; Bertoletti, L.; Douplat, M.; Dargaud, Y.; Grange, C.; Lobbes, H.; Provencher, S.; Lega, J.-C. Arterial and Venous Thromboembolism in COVID-19: A Study-Level Meta-Analysis. Thorax 2021. [Google Scholar] [CrossRef]
  87. Weitz, J.I.; Fredenburgh, J.C.; Eikelboom, J.W. A Test in Context: D-Dimer. J. Am. Coll. Cardiol. 2017, 70, 2411–2420. [Google Scholar] [CrossRef]
  88. Calabrò, P.; Gragnano, F.; Golia, E.; Grove, E. Von Willebrand Factor and Venous Thromboembolism: Pathogenic Link and Therapeutic Implications. Semin. Thromb. Hemost. 2018, 44, 249–260. [Google Scholar] [CrossRef]
  89. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; **ang, H.; Cheng, Z.; **ong, Y.; et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020, 323, 1061. [Google Scholar] [CrossRef]
  90. Ji, R.; Cheng, Y.; Yue, J.; Yang, J.; Liu, X.; Chen, H.; Dean, D.B.; Zhang, C. MicroRNA Expression Signature and Antisense-Mediated Depletion Reveal an Essential Role of MicroRNA in Vascular Neointimal Lesion Formation. Circ. Res. 2007, 100, 1579–1588. [Google Scholar] [CrossRef]
  91. Gupta, M.P. Factors Controlling Cardiac Myosin-Isoform Shift during Hypertrophy and Heart Failure. J. Mol. Cell. Cardiol. 2007, 43, 388–403. [Google Scholar] [CrossRef] [Green Version]
  92. Gambardella, J.; Coppola, A.; Izzo, R.; Fiorentino, G.; Trimarco, B.; Santulli, G. Role of Endothelial MiR-24 in COVID-19 Cerebrovascular Events. Crit. Care 2021, 25, 306. [Google Scholar] [CrossRef]
  93. Mone, P.; Gambardella, J.; Wang, X.; Jankauskas, S.S.; Matarese, A.; Santulli, G. MiR-24 Targets the Transmembrane Glycoprotein Neuropilin-1 in Human Brain Microvascular Endothelial Cells. Noncoding RNA 2021, 7, 9. [Google Scholar] [CrossRef] [PubMed]
  94. Maillard, P.V.; Ciaudo, C.; Marchais, A.; Li, Y.; Jay, F.; Ding, S.W.; Voinnet, O. Antiviral RNA Interference in Mammalian Cells. Science 2013, 342, 235–238. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Morales, L.; Oliveros, J.C.; Fernandez-Delgado, R.; ten Oever, B.R.; Enjuanes, L.; Sola, I. SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology. Cell Host Microbe 2017, 21, 344–355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Khan, M.; Sany, M.; Us, R.; Islam, M.; Islam, A.B.M.M. Epigenetic Regulator MiRNA Pattern Differences Among SARS-CoV, SARS-CoV-2, and SARS-CoV-2 World-Wide Isolates Delineated the Mystery Behind the Epic Pathogenicity and Distinct Clinical Characteristics of Pandemic COVID-19. Front. Genet. 2020, 11, 765. [Google Scholar] [CrossRef]
  97. Liu, Z.; Wang, J.; Xu, Y.; Guo, M.; Mi, K.; Xu, R.; Pei, Y.; Zhang, Q.; Luan, X.; Hu, Z.; et al. Implications of the Virus-Encoded MiRNA and Host MiRNA in the Pathogenicity of SARS-CoV-2. ar**v 2020, ar**v:2004.04874. [Google Scholar]
  98. Yousefi, H.; Poursheikhani, A.; Bahmanpour, Z.; Vatanmakanian, M.; Taheri, M.; Mashouri, L.; Alahari, S.K. SARS-CoV Infection Crosstalk with Human Host Cell Noncoding-RNA Machinery: An in-Silico Approach. Biomed. Pharmacother. 2020, 130, 110548. [Google Scholar] [CrossRef]
  99. Meng, F.; Siu, G.K.-H.; Mok, B.W.-Y.; Sun, J.; Fung, K.S.C.; Lam, J.Y.-W.; Wong, N.K.; Gedefaw, L.; Luo, S.; Lee, T.M.H.; et al. Viral MicroRNAs Encoded by Nucleocapsid Gene of SARS-CoV-2 Are Detected during Infection, and Targeting Metabolic Pathways in Host Cells. Cells 2021, 10, 1762. [Google Scholar] [CrossRef]
  100. Bartoszewski, R.; Dabrowski, M.; Jakiela, B.; Matalon, S.; Harrod, K.S.; Sanak, M.; Collawn, J.F. SARS-CoV-2 May Regulate Cellular Responses through Depletion of Specific Host MiRNAs. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2020, 319, L444–L455. [Google Scholar] [CrossRef]
  101. Zhang, X.; Zhou, Y.; Chen, S.; Li, W.; Chen, W.; Gu, W. LncRNA MACC1-AS1 Sponges Multiple MiRNAs and RNA-Binding Protein PTBP1. Oncogenesis 2019, 8, 73. [Google Scholar] [CrossRef]
  102. Kamel, W.; Noerenberg, M.; Cerikan, B.; Chen, H.; Järvelin, A.I.; Kammoun, M.; Lee, J.Y.; Shuai, N.; Garcia-Moreno, M.; Andrejeva, A.; et al. Global Analysis of Protein-RNA Interactions in SARS-CoV-2-Infected Cells Reveals Key Regulators of Infection. Mol. Cell 2021, 81, 2851–2867.e7. [Google Scholar] [CrossRef]
  103. Srivastava, R.; Daulatabad, S.V.; Srivastava, M.; Janga, S.C. Role of SARS-CoV-2 in Altering the RNA-Binding Protein and MiRNA-Directed Post-Transcriptional Regulatory Networks in Humans. IJMS 2020, 21, 7090. [Google Scholar] [CrossRef] [PubMed]
  104. Phillips, N. The Coronavirus Is Here to Stay—Here’s What That Means. Nature 2021, 590, 382–384. [Google Scholar] [CrossRef] [PubMed]
Ncrna 07 00054 g001 550
Figure 1. NF-κB amplification of the immune-activating signal is an integration of ncRNA regulation. (a) A negative feedback loop of immunosuppressive ncRNA regulatory balance: NF-κB signaling induces the transcription of miR-146a-5p, which inhibits IRAK1, a positive regulator of NF-κB-promoted genes. The result is the downregulation of inflammatory gene expression, such as IL-6, IL-1β, and IRAK1. The lincRNA PVT1 is associated with promoter CpG methylation and thus the downregulation of miR-146a-5p expression, blocking its immunosuppressive expression; (b) a positive feedback loop of inflammatory ncRNA regulatory balance: NF-κB signaling induces the transcription of miR-155-5p, which further amplifies NF-κB signaling via IKK and PI3K/Akt, leading to the production of the inflammatory molecules IL-6, IL-1β, and IRAK1. Dexamethasone treatment can block miR-155-5p transcription by inhibiting NF-κB signalling.
Figure 1. NF-κB amplification of the immune-activating signal is an integration of ncRNA regulation. (a) A negative feedback loop of immunosuppressive ncRNA regulatory balance: NF-κB signaling induces the transcription of miR-146a-5p, which inhibits IRAK1, a positive regulator of NF-κB-promoted genes. The result is the downregulation of inflammatory gene expression, such as IL-6, IL-1β, and IRAK1. The lincRNA PVT1 is associated with promoter CpG methylation and thus the downregulation of miR-146a-5p expression, blocking its immunosuppressive expression; (b) a positive feedback loop of inflammatory ncRNA regulatory balance: NF-κB signaling induces the transcription of miR-155-5p, which further amplifies NF-κB signaling via IKK and PI3K/Akt, leading to the production of the inflammatory molecules IL-6, IL-1β, and IRAK1. Dexamethasone treatment can block miR-155-5p transcription by inhibiting NF-κB signalling.
Ncrna 07 00054 g001
Table
Table 1. A summary of the published COVID-19 ncRNA profiling studies with relevant literature highlighted.
Table 1. A summary of the published COVID-19 ncRNA profiling studies with relevant literature highlighted.
StudyncRNA of InterestEffect on ncRNA from InfectionContext InvestigatedAdditional Findings
[19]miR-766-3pDownregulatedCOVID-19 patients
  • ▪ miR-766-3p was also downregulated in arthritis patients where patients upregulated IL-6 [20].
  • ▪ miR-766-3p overexpression reduced IL-6 expression in a cell line-immune stimulation model [21].
miR-1275DownregulatedCOVID-19 patients
  • ▪ TNF-α and IL-6 treatment of adipocytes reduced miR-1275 expression.
  • ▪ miR-1275 has NF-κB binding sites.
miR-31-5pUpregulatedCOVID-19 patients
  • ▪ miR-31 was overexpressed in keratinocytes from patients with psoriasis (inflammatory condition) [22].
  • ▪ miR-31 silencing also suppressed the ability of keratinocytes to recruit immune cells.
  • ▪ miR-31 was found to inhibit STK40, an immunosuppressive protein.
  • ▪ However, miR-31 is also associated with TNS1 downregulation, an enhancer of immune infiltration [23].
  • ▪ Additionally, miR-31 knockdown worsened inflammation in a mouse inflammatory bowel disease model [24].
[25]miR-146a-5pDownregulatedCOVID-19 patients
  • ▪ miR-146a-5p was upregulated in patients that responded to tocilizumab treatment. Those who were unresponsive downregulated it [25].
  • ▪ miR-146a-5p was found to downregulate IL-6 expression [26].
  • ▪ miR-146a-5p was also found to downregulate IL-1β and IRAK1 expression [27].
[28]PVT1UpregulatedCOVID-19 patients
  • ▪ PVT1 promotes the CpG methylation of the miR-146a promoter, suppressing expression [29].
  • ▪ PVT1 was also upregulated in the synovial tissue of arthritis patients [30].
[31]MALAT1UpregulatedSARS-CoV-2 infected NHBE cells (bronchial)
  • ▪ MALAT1 can enhance immune cell chemotaxis by recruiting p300, reducing IL-8 expression [32].
[33]MALAT1Downregulated Mild COVID-19 patients—monocytes and macrophages
  • ▪ MALAT1 expression is associated with macrophage differentiation into the inflammatory M1 subtype [34]. These mildly affected patients may be exhibiting protection [33].
MALAT1UpregulatedMild COVID-19 patients–CD4+ T cells
  • ▪ MALAT1 loss activates CD4+ T cells, pushing the balance away from regulatory T differentiation, instead towards the Th1 and Th17 effector type [35].
  • ▪ MALAT1 mouse knockouts have more immune activation in infection [17].
MALAT1DownregulatedSevere COVID-19 patients—CD4+ T cells
NEAT1DownregulatedMild COVID-19 patients—BAL cells
  • ▪ NEAT1 enhances the assembly and processing of inflammasomes in macrophages; thus, its expression is likely pro-inflammatory [36].
NEAT1UpregulatedSevere COVID-19 patients—BAL cells
[37]miR-26a-5pDownregulatedCOVID-19 patients
  • ▪ miR-26a-5p downregulation correlated with IL-6 and ICAM-1 upregulation in the study patients [37].
  • ▪ miR-26a-5p overexpression improved lung disease in an LPS-induced infection mouse model, likely by reducing inflammatory cytokine expression [38].
  • ▪ However, miR-26a-5p is correlated with increased IL-1β, IL-6, and TNF-α expression in macrophages from diabetic mice [39].
miR-29-3pDownregulatedCOVID-19 patients
  • ▪ miR-29-3p downregulation is correlated with IL-4 and IL-8 upregulation in the study patients [37].
  • ▪ miR-29-3p acted as anti-inflammatory by reducing MAPK activation and NF-κB signalling after LPS stimulation in a rat model of sepsis [40].
  • ▪ However, miR-29-3p was thought to promote IL-8 and other cytokine expression in a mouse respiratory disease model [41].
[42]miR-103aDownregulatedHigher D-dimer COVID-19 patients
  • ▪ miR-103a was downregulated in another study of patients with thromboembolic events [43].
  • ▪ miR-103a promotes M2 polarization, an immunosuppressive macrophage subtype [44].
miR-145DownregulatedHigher D-dimer COVID-19 patients
  • ▪ miR-145′s predicted target is the tissue factor (TF) [45].
  • ▪ Restoring miR-145 in a thrombotic animal model decreased TF and reduced thrombogenesis [46].
  • ▪ miR-145 was also reduced in patients with thromboembolic events and was negatively correlated with TF levels [46].
miR-885DownregulatedHigher D-dimer COVID-19 patients
  • ▪ miR-885′s predicted target is the von Willebrand Factor (vWF) [47].
  • ▪ ADAMTS13/vWF is correlated with thromboembolic incidence in COVID-19, and higher vWF is correlated with high D-dimer levels [48]
miR-424UpregulatedHigher D-dimer COVID-19 patients
  • ▪ miR-424 was also upregulated in two other studies of thromboembolic patients [49,50].
  • ▪ miR-424 may promote monocyte differentiation [51].
[52]miR-21UpregulatedCOVID-19 patients
  • ▪ A mouse model of cardiac hypertrophy exhibited a four-fold increase in miR-21 [53].
  • ▪ Antisense miR-21 depletion in cultured heart cells improved their hypertrophic state [53].
  • ▪ miR-21 potentiated ERK–MAPK activity by inhibiting sprout homologue 1, inducing cardiac fibrosis and dysfunction [54].
  • ▪ However, miR-21 overexpression improved fibrosis and symptoms in mice with cardiac infarctions [55].
miR-155UpregulatedCOVID-19 patients
  • ▪ miR-155 activates NF-κB signaling by activating IKK and PI3K/Akt [56]
miR-208aUpregulatedCOVID-19 patients
  • ▪ miR-208a is cardiac-specific [57].
  • ▪ miR-208 knockout mice did not develop fibrosis or hypertrophy in a heart disease model [58].
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Plowman, T.; Lagos, D. Non-Coding RNAs in COVID-19: Emerging Insights and Current Questions. Non-Coding RNA 2021, 7, 54. https://doi.org/10.3390/ncrna7030054

AMA Style

Plowman T, Lagos D. Non-Coding RNAs in COVID-19: Emerging Insights and Current Questions. Non-Coding RNA. 2021; 7(3):54. https://doi.org/10.3390/ncrna7030054

Chicago/Turabian Style

Plowman, Tobias, and Dimitris Lagos. 2021. "Non-Coding RNAs in COVID-19: Emerging Insights and Current Questions" Non-Coding RNA 7, no. 3: 54. https://doi.org/10.3390/ncrna7030054

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop