The Great Deceiver: miR-2392’s Hidden Role in Driving SARS-CoV-2 Infection

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 positive patients, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we have developed a novel miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters and may potentially inhibit a COVID-19 disease state in humans.

SciScore for 10.1101/2021.04.23.441024: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Ethics	not detected.
Sex as a biological variable	not detected.
Randomization	not detected.
Blinding	not detected.
Power Analysis	not detected.
Cell Line Authentication	not detected.

Table 2: Resources

Experimental Models: Cell Lines
Sentences	Resources
Publicly available RNA-seq data: A549, Calu-3, NHBE, and COVID-19 lung biopsy: Raw RNA-seq read counts from the publication by Blanco-Melo et al. for the A549, Calu-3, and NHBE cell lines as well as post-mortem lung biopsies from two COVID-19 patients were downloaded from the Gene Expression Omnibus (series accession GSE147507) (Blanco-Melo et al., 2020).	A549 suggested: None Calu-3 suggested: None
miR-2392 mimic experiments in SH-SY5Y cells and RNA-seq: RNA was …

SciScore for 10.1101/2021.04.23.441024: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Ethics	not detected.
Sex as a biological variable	not detected.
Randomization	not detected.
Blinding	not detected.
Power Analysis	not detected.
Cell Line Authentication	not detected.

Table 2: Resources

Experimental Models: Cell Lines
Sentences	Resources
Publicly available RNA-seq data: A549, Calu-3, NHBE, and COVID-19 lung biopsy: Raw RNA-seq read counts from the publication by Blanco-Melo et al. for the A549, Calu-3, and NHBE cell lines as well as post-mortem lung biopsies from two COVID-19 patients were downloaded from the Gene Expression Omnibus (series accession GSE147507) (Blanco-Melo et al., 2020).	A549 suggested: None Calu-3 suggested: None
miR-2392 mimic experiments in SH-SY5Y cells and RNA-seq: RNA was dissolved in nuclease free water and concentration determined spectrometrically at 260nm using a Biotek plate reader (Biotek).	SH-SY5Y suggested: None
Software and Algorithms
Sentences	Resources
Publicly available Bronchial Alveolar Lavage Fluid (BALF) COVID-19 RNA-sequencing data: Fastq files were downloaded from SRA (NCBI BioProject PRJNA605907 (Shen et al., 2020) and NCBI BioProject PRJNA390194 (Ren et al., 2018)).	BioProject suggested: (NCBI BioProject, RRID:SCR_004801)
Data were then aligned using STAR (v2.7.3) two pass mode to the Human reference genome (GRCh38 v99 downloaded 04-27-2020).	STAR suggested: (STAR, RRID:SCR_004463)
Unaligned data were written to a fastq file, and then realigned to the GRCh38 reference genome using Bowtie 2 (v2.3.4.1), and output sam file converted to a bam file using samtools (v1.7).	samtools suggested: (SAMTOOLS, RRID:SCR_002105)
Publicly available RNA-seq data: A549, Calu-3, NHBE, and COVID-19 lung biopsy: Raw RNA-seq read counts from the publication by Blanco-Melo et al. for the A549, Calu-3, and NHBE cell lines as well as post-mortem lung biopsies from two COVID-19 patients were downloaded from the Gene Expression Omnibus (series accession GSE147507) (Blanco-Melo et al., 2020).	Gene Expression Omnibus suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
Final libraries were quantified using fluorescent-based assays including PicoGreen (Life Technologies) or Qubit Fluorometer (Invitrogen) and Fragment Analyzer (Advanced Analytics) and sequenced on a NovaSeq 6000 sequencer (v1 chemistry) with 2×150bp targeting 60M reads per sample.	PicoGreen suggested: None

Results from OddPub: Thank you for sharing your code and data.

Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

Identifier	Status	Title
NCT04475601	Recruiting	Enzalutamide Treatment in COVID-19
NCT04604223	Recruiting	Effect of Pioglitazone on T2DM Patients With COVID-19

Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 42. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

Results from rtransparent:

Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
No protocol registration statement was detected.

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The Great Deceiver: miR-2392’s Hidden Role in Driving SARS-CoV-2 Infection

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