COVID-19 Genetics: Study Shows How Human Host Micro-RNAs Affects SARS-CoV-2 Infections

COVID-19 Genetics: The current COVID-19 pandemic has infected almost 60 million people worldwide and caused more than 1.4 million deaths. These figures are rising exponentially but as far as progress is concerned in terms of finding a cure for the disease, we are still nowhere as unknown to many, the COVID-19 disease is a highly complex disease that is not just affected by the type or strain of SARS-CoV-2 coronavirus affecting a person but the pathogenesis and disease progression is dependent on a variety of factors including existing comorbidities in person, the state of their immune system, hereditary genes and also a host of other gene variants in the human host including human micro-RNAs .


 
In the past ten months, much has been discovered about the novel SARS-CoV-2 coronavirus; its capacity to infect human host cells, its varying effects on infected individuals and the dynamics of its transmission from one person to another. But even while we discovered new facets about the virus and the disease each day, the novel coronavirus itself is evolving at a fast rate and creating new scenarios much to the surprise of researchers.
 
A team of scientists and genetic and genomic experts based in Iran have explored the role of micro-RNA in COVID-19.
 
The innate and adaptive immune systems have a pivotal role in the fate of viral infections, such as COVID-19 pandemic. MicroRNAs (miRNAs) are known as short noncoding RNA molecules and appear as indispensable governors of almost any cellular means. Several lines of evidence demonstrate that miRNAs participate in essential mechanisms of cell biology, regulation of the immune system, and the onset and progression of numerous types of disorders. The immune responses to viral respiratory infections (VRIs), including influenza virus (IV), respiratory syncytial virus (RSV), and rhinovirus (RV), are correlated with the ectopic expression of miRNAs. Alterations of the miRNA expression in epithelial cells may contribute to the pathogenesis of chronic and acute airway infections.
 
Hence, analyzing the role of these types of nucleotides in antiviral immune responses and the characterization of miRNA target genes might contribute to understanding the mechanisms of the interplay between the host and viruses, and in the future, potentially result in discovering therapeutic strategies for the prevention and treatment of acute COVID-19 infection.
 
In this study, the researchers  present a general review of current studies concerning the function of miRNAs in different VRIs, particularly in coronavirus infection, and address all available therapeutic prospects to mitigate the burden of viral infections.
 
The study findings were published in the peer reviewed journal International Immunopharmacology. https://www.sciencedirect.com/science/article/pii/S1567576920336717?via%3Dihub
 
The SARS-CoV-2 is a betacoronavirus, which is an enveloped virus with a positive-sense single-stranded RNA. It belongs to the coronaviridae family, and like others of its kind, typically causes a respiratory tract infection (RTI).
 
So called micro-RNAs or miRNAs are essentially small molecules about 17 and 24 nucleotides in length. These are non-coding, single-stranded RNAs that are needed for the translation of mature messenger RNAs (mRNAs) into proteins.
 
The study team notes that these miRNAs play a role in various processes such as “cell propagation, differentiation, growth, and apoptosis.” These miRNAs also regulate the innate and adaptive immune systems. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662938/
 
Previous studies have shown that the expression of these miRNAs can play a role in the host’s response to coronaviruses and other respiratory viruses. https://www.tandfonline.com/doi/abs/10.1586/1744666X.2014.913482
 
According to the study team, “Changes in miRNA expressions within the epithelial cells of the host can contribute to “the pathogenesis of both severe and chronic respiratory infections.”
 
This study looked at the role played by these miRNAs as available from scientific evidence.
 
It was found that when exposed to an infection such as the SARS-CoV-2, humoral immunity is activated. The T cells and B cells differentiate into plasma cells that produce antibodies (Abs) against the particular viral antigen (Ag). These Abs then stop the virus from entering the host cells. https://link.springer.com/chapter/10.1007/978-981-15-4814-7_5
 
https://www.dl.begellhouse.com/en/journals/2ff21abf44b19838,11507d0223641194,73e43c4866fa4682.html
 
https://journals.lww.com/infectdis/Abstract/2017/01000/Prevalence_of_atlE,_ica,_mecA,_and_mupA_Genes_in.10.aspx
 
https://link.springer.com/chapter/10.1007/978-981-15-4814-7_5
 
The B and T cells produce Abs against the SARS-CoV-2’s “spike (S), nucleocapsid (N), membrane (M), and envelope (E) proteins (structural proteins).”
 
The study team says that the T helper 1 (Th1) response is important for control of both MERS-CoV and SARS-CoV-1 and other coronaviruses in the same family as SARS-CoV-2 and possibly SARS CoV-2 itself. https://www.frontiersin.org/articles/10.3389/fmicb.2019.01781/full
 
It is known that cytokine storm syndrome (CSS) is caused when massive amounts of proinflammatory cytokines are released by the activated immune cells. CSS is one of the complications of COVID-19 and often causes severe disease or even death if initiated.
 
The study team writes, “ARDS (Acute Respiratory Distress Syndrome) is highly correlated with CSS as the immune effector cells secrete high amounts of proinflammatory cytokines and chemokines during ARDS, leading to the uncontrolled systemic inflammatory responses.”
 
The team explained that CSS induced ARDS causes multiple organ failure and subsequent death. https://www.sciencedirect.com/science/article/pii/S0009898120302813
 
It was found that when a virus or pathogen infects a person, the first immune response is from innate immunity. The miRNA regulates the functions of the various immune cells such as the “dendritic cells, epithelial cells, monocytes, granulocytes, NK cells, and macrophages.” https://www.tandfonline.com/doi/abs/10.1586/1744666X.2014.913482
 
The key roles of some fo the human host miRNAs from the study and existing literature can be summarized as follows:
 
-miRNAs participate in signal transduction of TLRs (toll-like receptors a specialized transmembrane protein)
 
-miR-146a and miR-146b are expressed in higher amounts when lipopolysaccharide (LPS) on the cell membranes are exposed to the THP-1 cell line. TLR signaling pathways are activated when exposed to fungal, viral, and bacterial agonists.
 
-miR-155 is also a regulator of the pro-inflammatory cytokines
 
-miR-146a also modulates the TLR signaling pathway
 
-The generation of cytokines, such as TNF-α, IL-6, and IL-12, are reduced when the miR-152 and miR-148 are induced.
 
-miRNAs regulate the central-adaptive immune responses
 
-miR-181a in immature T cells can modulate T-cell receptor signal transduction
 
-Numerous studies have shown that miR-155 and miR-128 regulate the innate immune responses against respiratory viruses. When these miRNAs are removed, the host is susceptible to these viruses.
 
-In-silico examination of miRNAs interacting with SARS-CoV-1 mRNAs shows that there is an upregulation of miR-214, miR-574-5p, and miR-17 that inhibits viral replication
 
-With MERS-CoV, the miRNAs downregulate the viral gene expression and thus prevent its replication
 
-The miR-32 is the target of the viral RNA genome in SARS CoV-2. The team writes, “Several lines of evidence showed that viral pathogens could evade the immune system surveillance by utilizing the host miRNAs.”
 
-To date, there are no drugs that can increase/inhibit any miRNAs in viral infections


The antiviral immune response and role of miRNAs. TLR, Toll-like receptor; RIG1, Retinoic acid-inducible gene I; MAD5, melanoma differentiation-associated protein 5; Mitochondrial antiviral-signaling protein; TRAF3, TNF receptor-associated factor3; TRAF6, TNF receptor-associated factor6; IKK, I?B kinase; TANKbinding kinase 1; IRF3, Interferon regulatory factor 3; IFN, Interferon; IFNAR1, interferon-a/ß receptor 1; STAT1, Signal transducer and activator of transcription 1; STAT2, Signal transducer and activator of transcription 2; IRF9, Interferon regulatory factor 9; ISG, interferon-stimulated gene; miRNAs, microRNAs.
 
The study shows that miRNAs play a significant role in viral control of several cellular processes seen during viral infections.
 
Importantly the activity of the miRNAs can determine the severity of COVID-19.
 
Human host miRNAs, the study shows, can promote infection and can also act as an antiviral, depending on its type.
 
The study team concluded, “MiRNAs can act as a means of preventing, diagnosing and curing viral infections,” and provide scope for research in the development of effective treatment for COVID-19.
 
Countless numbers of human miRNAs appear to be capable of targeting viral genes and their functions, including interfering with replication, translation, and expression. The dual function of host cellular miRNAs cannot be underestimated in the viral replication or inhibition. Host miRNAs may have an antiviral role, which is useful by the host, or might promote viral replication and infection by miRNA-viral genome interaction. Finally, future investigations on the role of miRNAs in respiratory viral infections can open up a new horizon for the application of miRNAs to prevent, diagnose, and cure viral infections.
 
Table 1. Role of microRNAs in viral respiratory infections.

MicroRNA	Viral infection	Effect	Ref
hs-miR-a, miR-b	Human rhinovirus	The levels of hs-miR-a and hs-miR-b were reliant on HRV replication.
miR-128, miR-155	human rhinovirus	The bioinformatics investigation indicated that the miR-128 and miR-155 contribute to the innate immune response toward HRV-1B.
miR-23b	human rhinovirus	The RIG-I- like receptor-inducible miRNAs, miR-23b, hinders infections HRV-1B by decreasing the very low-density lipoprotein receptor.
miR-323, miR-491, miR-654	influenza virus	The mutational examination determined that miR-323, miR-491, and miR-654 were increased following H1N1 infection.
miR-17-3p, miR-221	influenza virus	The expression levels of miR-17-3p and miR-221 decreased in human alveolar basal epithelial cells (HBEpC) through the initial step of IAV infection.
let-7c	influenza virus	The miR-let-7c expression was remarkably raised in IV-infected A549 cells.
let-7f	human metapneumovirus	Following RSV infection, the let-7f expression was significantly increased.
miR-185–5p	human metapneumovirus	The hMPV provokes miR-185–5p expression.
miR-16	human metapneumovirus	During hMPV infection, has-miR-185–5p expression was increased. hMPV (Wild type) infection does not provoke miR-30a and miR-16 expression, but the virus deficient the M2-2 gene enhancing miR-16 and miR-30a.
miR-374a, miR-192	human metapneumovirus	The miR-374a* was diminished by hMPV infection.
miR-221	respiratory syncytial virus	The RSV infection significantly diminished the expression of miR-221.
miR-30, let-7i	respiratory syncytial virus	The expression of let-7i was observed in healthy HBEpC cultures infected with an RSV that deficient NS1 and NS2 proteins.
let-7	respiratory syncytial virus	The increase in the expression of let-7b was observed in HBEpC cultures infected with an RSV.
miR-339-5p	respiratory syncytial virus	Following the RSV infection, miR-339-5p targets the TrKB and APAF1 genes and result in TrKB- Brain-derived Neurotrophic Factor binding as well as apoptosis.
miR-453	respiratory syncytial virus	During the RSV disease, the low-affinity p75 NTR receptor gene was declined via miR-453.
miR-34	respiratory syncytial virus	In patients infected with RSV, the expression levels of miR-34b and miR-34c were reduced.
miR-125	respiratory syncytial virus	Among the miR-125 family, in patients infected with RSV, the expression of miR-125a and miR-125c were reduced.
miR-29	respiratory syncytial virus	Among the human miR-29 family, the expression levels of miR-29c were declined in RSV infected patients contrasted to the control group.
miR-429	respiratory syncytial virus	According to the severity of the mild group's illness in patients infected with RSV, miR-429 levels were downregulated.
miR-27	respiratory syncytial virus	The miR-27 family was deregulated during RSV infection. For instance, the miR-27b is downregulated in patients infected with RSV.
miR-155	respiratory syncytial virus	miR-155 overexpressed in patients infected with RSV. This miR represses IFN pathways for reducing anti-viral status.
miR-31	respiratory syncytial virus	The miR-31 overexpressed in patients infected with RSV.

 
 
Table 2. MicroRNAs in coronaviruses infection.

MicroRNA	Coronavirus	Description	Ref
miR-9	OC43	The OC43 nucleocapsid protein, via direct interaction with mir-9, can modulate NF-kB expression.
miR-17, miR-223, miR-574-5p, miR-214, miR-223, miR-98	SARS	Viral Nucleocapsid and Spike protein reduced the expression of miR-223 and miR-98 within the BASC.
miR-16-1-3p, miR-26a-1-3p, miR-425-5p, miR-500b-5p, miR-627-5p, miR-1257, miR-1275, miR-2277-5p, miR-2392, miR-4448, miR-4455, miR-4521, miR-6807-5p, and miR-6847-3p, miR-329-5p, miR-539-5p, miR-619-5p, miR-762, and miR-6836-5p	MERS	The host ceRNA and circRNAs analysis in human lung adenocarcinoma epithelial cells contaminated with the highly pathogenic MERS-CoV indicated that MERS-CoV infection could impact on host gene expression.
miR628-5p, miR-6804-3p, miR-4289, miR-208a-3p, miR-510-3p, miR-18a-3p, miR-329-3p, miR-548ax, miR-3934-5p, miR-4474-5p, miR-7974, miR-6865- 5p, and miR-342-3p	MERS	The computational approach provided an exciting hypothesis that those miRNAs involved in MERS-CoV pathogenesis, and this approach may help to understand host-pathogen interplay better and promote new antiviral treatment toward MERS-CoV.
miR-146a-5p, -21-5p, and -126-3p	SARS-CoV-2	In patients with COVID-19 that not respond to the tocilizumab treatment, the levels of miR-146a-5p were decreased in the serum. Also, this study's data suggest miRs in the blood, such as miR-146a-5p, can act as biomarkers and provide a molecular link between inflammation and the COVID-19 clinical course.
miR-200c	SARS-CoV-2	Aa study investigated several identified miRNAs that could regulate ACE2 which may be exploited to regulate the SARS-CoV-2 receptor. Their data reveal that both ACE2 mRNA and ACE2 protein levels are inhibited by miR-200c in rat primary cardiomyocytes and, importantly, in human-derived cardiomyocytes
miR-98-5p	SARS-CoV-2	In a study evaluated the microRNAs that specifically target TMPRSS2. Through a bioinformatic approach, they identified miR-98-5p as a suitable candidate and they mechanistically validated miR-98-5p as a regulator of TMPRSS2 transcription in two different human endothelial cell types, derived from the lung and from the umbilical vein

 
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