key: cord-0874233-dtn7h1gj
authors: Haddad, Hazem; Walid Al-Zyoud
title: miRNA target prediction might explain the reduced transmission of SARS-CoV-2 in Jordan, Middle East
date: 2020-08-20
journal: Noncoding RNA Res
DOI: 10.1016/j.ncrna.2020.08.002
sha: 4fada4ada296bdbdf939923f3cd117993d2a0d47
doc_id: 874233
cord_uid: dtn7h1gj

MicroRNAs (miRNAs) are non-coding RNAs that control many functions within the human cells by controlling protein levels through binding to messenger RNA (mRNA) translation process or mRNA abundance. Many pieces of evidence show that miRNAs affect the viral RNA replication and pathogenesis through direct binding to the RNA virus to mediate changes in the host transcriptome. Many previous studies have been studying the interaction between human cells' miRNA and viral RNA to predict many targets along the viral genome. In this work, via the miRDB database, we determined the target scores of predicted human miRNA to bind with the ss-RNA of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in general and its spike gene in specific. Our predicted miRNA targets of the ss-RNA of SARS-CoV-2 might destabilize the ss-RNA translation of SARS-CoV-2 that has been established by more than 80% of asymptomatic infected cases in Jordan due to host miRNA interactions. In respiratory epithelial cells, the high prediction scoring for miRNAs covers the RNA from 5′ to 3′ that explains successful antiviral defenses against ss-RNA of SARS-CoV-2 and might lead to new nucleotide deletion mechanisms. The exciting findings here that the nucleotide substitution 1841A > G at the viral genomic RNA level, which is an amino acid substation D614G at the spike protein level showed a change in the predicted miRNA sequence from hsa-miR-4793-5p to hsa-miR-3620-3p with an increase in the target score from 91 to 92.

In 2003, severe coronavirus acute breathing syndrome (SARS-CoV) appeared in China. It has spread to over 30 countries, infecting around 8,000 people, killing young people with 10%, and aging with 50%. There are no approved coronavirus vaccines or antiviral treatments against, for example, such as the Middle East respiratory CoV (MERS-CoV) yet [2] . The molecular mechanisms of viral pathogenesis provide thoughtful help in the search for effective and secure therapeutic strategies against new human SARS-Cov-2.

MicroRNAs (miRNAs) are non-coding RNAs that control many functions within a cell by controlling protein levels through binding to mRNA translation process. Many shreds of evidence show that miRNAs affect the RNA viral replication and, consequently, pathogenesis through direct binding to the RNA virus-mediated changes in the host transcriptome. Host miRNAs can bind to a wide range of RNA viruses, straight adapt their pathogenesis through mimicking cellular mRNAs, and tolerating direct binding of the miRNA to the viral RNA.

Theoretically, the abovementioned regulation is analogous to that of the host mRNAs [3, 4] .

Many miRNA sequences that targeted Influenza viral RNA segments were linked with the activity of host miRNA-induced antiviral defense. This link represents potential treatment with a combination of five miRNAs through Antagomirs delivery to suppress the viral replication and effectively improve protection against lethal challenge with PR8 influenza virus strain in mice [5] .

Severe acute coronavirus syndrome (SARS-CoV) caused human fatal disease and reaction and extensive pulmonary disease. The significance of small non-coding RNAs for SARS-CoV pathologies, lung RNAs sequences of infected mice, and three (18 to 22nt) small viral RNAs (svRNAs) were discovered. The three svRNAs originated from the SARS-CoV genomic regions nsp3 (svRNA-nsp3.1 and -nsp3. 2) , and N (svRNA-N). CoV svRNAs were characterized as independent from cell type and host species RNase III, but the extent of the viral replication machinery was a dependent process. In vivo, lung pathology and proinflammatory cytokine release, antagomir-mediated inhibition of svRNA-N significantly decreased. This indicates that svRNAs contribute to the pathogenesis of SARS-CoV and demonstrates the potential for antagomirs of svRNA-N as antivirals [6] .

To understand the early steps of COVID-19 infection, we predicted miRNAs sequences targeting the submitted 29903bp of viral ss-RNA of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 complete genomic RNA sequence) from the isolate of Wuhan-Hu-J o u r n a l P r e -p r o o f 1. A predicted miRNAs targeting region at 3822 bp ss-RNA of the spike glycoprotein of SARS-CoV-2 was revealed. Also, we predicted miRNAs targeting a variable region of the ss-RNA spike glycoprotein of SARS-CoV-2 sequences from 20 positive nasopharyngeal specimens form Jordan. These specimens were collected and sequenced by Biolab Diagnostic Laboratories (Jordan) & Andersen lab at Scripps Research (USA), who deposited the sequences in GISAID, a maintained global database based in Germany. The perception in this work might help scientists to understand the molecular mechanisms of viral pathogenesis. Besides, it might support the research for effective, safe therapeutic strategies against known human coronaviruses and new emergent strains with a focus on miRNA-induced antiviral human body defense, which could be a potential treatment developed for SARS-CoV-2.

The miRDB is an online http:/mirdb.org/custom.html database for the target and working annotations of miRNA. All targets in miRDB were anticipated by MirTarget, a bioinformatics tool that was developed through the study of thousands of miRNA target interactions from high-performance research [7, 8] . 

We predicted top ten miRNAs targeting score between (98-99) against the submitted 29903 bp ss-RNA SARS-CoV-2 full length genome correspondingly, hsa-miR-4288, hsa-miR-195-5p, hsa-miR-16-5p, hsa-miR-15b-5p, hsa-miR-15a-5p, hsa-miR-6838-5p, hsa-miR-497-5p, hsa-J o u r n a l P r e -p r o o f miR-424-5p, hsa-miR-3133, hsa-miR-21-3p, please see Table 1 (Appendix). These miRNAs are presented in miRDB, along with associated function annotations. As a recent update, miRDB displays expressions of hundreds of cell lines, and the user may limit their search for the cell line of interest miRNA targets. miRDB offers an integrative analysis of the target prediction and ontological gene data found in Tables 2,3 target miRNA scored (91, 64 and 56) for (hsa-miR-4793-5p, hsa-miR-143-5p and hsa-miR-3133) respectively. The interesting finding here that the 1841A>G, and D614G showed a change in the predicted miRNA and an increase in the target score from 91 to 92 (hsa-miR-4793-5p to hsa-miR-3620-3p). However, the original and 3415G>T D1139Y showed the same sequence of the miRNA (hsa-miR-548g-3p) and an increase in the target score from 80 to 81.

The last substitution of 3499 G>A G1167S showed the same miRNA sequence of (hsa-miR-155-5p) and a decrease in the target score from 73 to 72.

One of the record genomic changes observed in the severe acute respiratory syndrome coronavirus (SARS-CoV-1) isolated from humans after human to human transmission was the acquisition of a specific 29-nucleotide deletion occurred in open reading frame 8 (ORF8). Three top target scores of miRNAs prediction (hsa-miR-497-5p, hsa-miR-195-5p and hsa-miR-21-3p) showed in Table 12 , 16 and 24 (Appendix). They had an expression in the respiratory epithelial cells, and effective antiviral defenses against the ss-RNA of SARS-CoV-2 might lead to a new J o u r n a l P r e -p r o o f mechanism of interaction binding miRNA to cause nucleotide deletion in SARS-CoV-2 in reflection to previous reports [5] [6] & [9] .

Over the past few years, some articles reported the target prediction of miRNA and viral RNA interaction. In our forecasts, more than asymptomatic 80% of the COVID-19 diseased persons 

Fund: any funding body did not fund this work. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Target Rank   Target Score  miRNA Name   1  92  hsa-miR-510-3p  2  90  hsa-miR-624-5p  14  84 hsa-miR-497-5p 

A new coronavirus associated with human respiratory disease in China

Update on replication and pathogenesis

RNA viruses can hijack vertebrate microRNAs to suppress innate immunity

MicroRNA Regulation of RNA Virus Replication and Pathogenesis

Endogenous Cellular MicroRNAs Mediate Antiviral Defense against Influenza A Virus

SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology

miRDB: an online database for prediction of functional microRNA targets

Prediction of functional microRNA targets by integrative modeling of microRNA binding and target expression data

The 29-Nucleotide Deletion Present in Human but Not in Animal Severe Acute Respiratory Syndrome Coronaviruses Disrupts the Functional Expression of Open Reading Frame 8

Acknowledgment: authors would like to acknowledge Jordanain Minsitry of Health and the Biolabs medical laboratories in Amman, Jordan, and their partners for depositing the SARS-CoV-2 sequences from Jordanian specimens at GISAID database.