Commentary
The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak was occurred in December 2019 [1]. Coronavirus disease 2019 (COVID-19) was considered a pandemic by the WHO on 12 March 2020. So far, many attempts have been made to design effective antiviral agents and vaccines against SARS-CoV-2. Current studies discussed ACE2, which plays an essential role in the pathophysiology of COVID-19 as a virus receptor [2]. According to studies finding, respiratory microbiota has been considered a notable factor in viral infections [3]. The human respiratory microbiota carries a wide range of gram-positive and gram-negative bacterial cells as the main composition, with different roles in physiological conditions and respiratory diseases [4].
Recent studies have suggested the role of respiratory microbiota in COVID-19 [5]. This commentary's hypothesis is based on the cellular function of gram-positive and gram-negative respiratory bacteria as a co-factor to prevent the expression of ACE2 and thus inhibit SARS-CoV-2. Lipopolysaccharide (LPS) is the outer membrane component in gram-negative bacteria [6]. Also, lipoteichoic acid (LTA) is the primary cell wall constituent in gram-positive bacteria [6]. Bacterial LPS and LTA can be involved in various cellular signaling mechanisms and pathways, including microRNA expression [7]. MicroRNAs are the small non-coding RNAs that impact viral respiratory infections pathogenesis [8]. Besides, the role of microRNAs as therapeutic agents and vaccine design has been discussed [8].
According to evidence, LPS activates NF-κB via TLR4 and LTA via TLR2 [7]. On the other hand, activation of the NF-κB pathway increases the expression of miR-200c-3p, which is an important factor in ARDS [7]. Increased expression of miR-200c-3p has been observed to decrease ACE2 expression [7]. It should be noted that low expression of ACE2 in the lungs and the upper respiratory tract in some COVID-19 cases may be associated with a reduction in disease severity [9]. Therefore, it is hypothesized that bacterial LPS and LTA can reduce the expression of ACE2 in the lungs of COVID-19 patients through upregulation of miR-200c-3p.
Murine models of SARS-CoV have confirmed that the virus may stimulate TNF-α and IL-6 through the NF-κB pathway[10]. Shaath et al. reported, NF-κB was activated in B.A.L. cells of severe COVID-19 [11]. This issue would clarify the high levels of cytokine responses, leading to inflammation and cytokines storm in COVID-19 patients. The cytokines storm in COVID-19 could result in ARDS and multi-organ dysfunction. This aspect could help in the design of effective vaccine and therapeutic approaches [10, 12]. Respiratory bacterial can also develop NF-κB activation, which induces a pro-inflammatory response in epithelial cells [13, 14]. The human microbiota can be altered after SARS-CoV-2 infection [15]. It is a hypothesis that these microbiota changes can illustrate the cytokines storm progression in COVID-19. Therapy using NF-κB inhibitor drugs leads to decreased inflammation and lung injury in SARS-CoV-infection models [16]. The differential miRNA expression in COVID-19 patients may regulate the inflammatory responses during infection [17]. Also, Some miRNAs can target ACE2 [18]. The “microRNA targeting” as anti-inflammatory agents should be carefully considered. It is well known that microRNAs are strongly involved in cytokines and chemokines expression, leading to cytokines storm in COVID-19 [19].
In conclusion, the composition of bacterial respiratory microbiota can be an indicator of COVID-19 severity. Future clinical trials are needed to investigate the role of probiotics containing LPS and LTA in affect on COVID-19 symptoms by upregulation miR-200c-3p levels and downregulation ACE2 levels in COVID-19 patients. Future studies in the gene therapy field could also directly investigate the role of miR-200c-3p as a biomarker in reducing ACE2 expression and COVID-19 severity to provide immunity against SARS-CoV-2.
Authors contribution
SS: literature search, writing, design, editing, and final proof. MZ: Editing and final proof.
Declarations
Conflict of interest
The authors have no conflict of interest to declare.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
5/26/2021
The term LPA was changed to LPS.
References
- 1.Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Li Y, et al. Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacol Res. 2020;157:104833. doi: 10.1016/j.phrs.2020.104833. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pichon M, Lina B, Josset LJV. Impact of the respiratory microbiome on host responses to respiratory viral infection. Vaccines(Basel) 2017;5(4):40. doi: 10.3390/vaccines5040040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Dickson RP, Erb-Downward JR, Huffnagle GB. The role of the bacterial microbiome in lung disease. Expert Rev Respir Med. 2013;7(3):245–257. doi: 10.1586/ers.13.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Khatiwada S, Subedi AJ. Lung microbiome and coronavirus disease 2019 (COVID-19): possible link and implications. Hum Microb J. 2020;17:100073. doi: 10.1016/j.humic.2020.100073. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Takeuchi O, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 1999;11(4):443–451. doi: 10.1016/S1074-7613(00)80119-3. [DOI] [PubMed] [Google Scholar]
- 7.Liu Q, et al. miRNA-200c-3p is crucial in acute respiratory distress syndrome. Cell Discovery. 2017;3(1):1–17. doi: 10.1038/s41421-019-0132-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Leon-Icaza SA, Zeng M, Rosas-Taraco AGJE. microRNAs in viral acute respiratory infections: immune regulation, biomarkers, therapy, and vaccines. ExRNA. 2019;1(1):1–7. doi: 10.1186/s41544-018-0004-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Yang C, Li Y, Xiao S-YJE. Differential expression of ACE2 in the respiratory tracts and its relationship to COVID-19 pathogenesis. EBio Med. 2020 doi: 10.1016/j.ebiom.2020.103004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Wang W, et al. Up-regulation of IL-6 and TNF-α induced by SARS-coronavirus spike protein in murine macrophages via NF-κB pathway. Virus Res. 2007;128(1–2):1–8. doi: 10.1016/j.virusres.2007.02.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Shaath H, et al. Single-cell transcriptome analysis highlights a role for neutrophils and inflammatory macrophages in the pathogenesis of severe COVID-19. Cell. 2020;9(11):2374. doi: 10.3390/cells9112374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Pearce L, Davidson SM, Yellon DM. The cytokine storm of COVID-19: a spotlight on prevention and protection. Expert Opin Ther Target. 2020;24(8):723–730. doi: 10.1080/14728222.2020.1783243. [DOI] [PubMed] [Google Scholar]
- 13.Stavropoulou E, et al. Unraveling the interconnection patterns across lung microbiome, respiratory diseases, and COVID-19. Front Cell Infect Microb. 2021;10:892. doi: 10.3389/fcimb.2020.619075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Medina E, Anders D, Chhatwal GS. Induction of NF-kappaB nuclear translocation in human respiratory epithelial cells by group A streptococci. Microb Pathag. 2002;33(6):307–313. doi: 10.1006/mpat.2002.0532. [DOI] [PubMed] [Google Scholar]
- 15.Soltani S, et al. The role of bacterial and fungal human respiratory microbiota in COVID-19 patients. Biomed Res Int. 2021 doi: 10.1155/2021/6670798. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Vitiello M, et al. NF-κB as a potential therapeutic target in microbial diseases. Mol Biosyst. 2012;8(4):1108–1120. doi: 10.1039/c2mb05335g. [DOI] [PubMed] [Google Scholar]
- 17.Li C, et al. Differential microRNA expression in the peripheral blood from human patients with COVID-19. J Clin Lab Anal. 2020;34(10):e23590. doi: 10.1002/jcla.23590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Hum C, et al. MicroRNA mimics or inhibitors as antiviral therapeutic approaches against COVID-19. Drugs. 2021;81:517–531. doi: 10.1007/s40265-021-01474-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Gasparello J, Finotti A, Gambari R. Tackling the COVID-19 “cytokine storm” with microRNA mimics directly targeting the 3’UTR of pro-inflammatory mRNAs. Med Hypothesis. 2021;146:110415. doi: 10.1016/j.mehy.2020.110415. [DOI] [PMC free article] [PubMed] [Google Scholar]