MicroRNAs as the Potential Regulators of SARS-CoV-2 Infection and Modifiers of the COVID-19 Clinical Features

Abstract

The pandemic of coronavirus disease 2019 warrants the identification of factors that may determine both risk and severity of infection. The factors include microRNAs that have a wide regulatory potential and hence are particularly interesting. The review focuses on the potential roles of human microRNAs and the viral genome as well as microRNAs in SARS-CoV-2 infection and clinical features of COVID-19. The review summarizes the information about the human microRNAs that are thought to specifically bind to the SARS-CoV-2 genome and considers their expression levels in various organs (cells) in both healthy state and pathologies that are risk factors for severe COVID-19. Potential mechanisms whereby SARS-CoV-2 may affect the clinical features of COVID-19 are discussed in brief. The mechanisms include blocking of human microRNAs and RNA-binding proteins, changes in gene expression in infected cells, and possible epigenetic modifications of the human genome with the participation of coronavirus microRNAs.

microRNA, the Innate-Immune System and SARS-CoV-2

“…There are also aging-, gender- and disease-associated effects on miRNA expression patterns in human biology. For example, some ‘beneficial’ human anti-viral miRNAs naturally down-regulated with aging may display modified SARS-CoV-2‐host cell interactions that enhance the severity and mortality among elderly COVID-19 patients, particularly those greater than 65 years of age ( Fulzele et al., 2020 ; Choe et al., 2022 ; Kucher et al., 2022 ; Lingor et al., 2022 ). When compared to normal cells and tissues, diseases such as cancer and AD display different intrinsic patterns of host miRNA expression throughout these disease processes.…”

“…Inter-current SARS-CoV-2 infection with these and other life-threatening/incapacitating diseases usually predict an unfavorable clinical outcome. One of the initial miRNA-based pharmaceuticals which specifically targets and down-regulates ssvRNA levels ( Miravirsen ; Santaris Pharma A/S/Hoffmann-La Roche-Genentech, San Francisco USA) is currently in Phase III clinical trials and there is emerging and supportive evidence that stabilized miRNAs have strong potential to down-regulate and/or neutralize viral replication, modulate the progress of viral infection and/or enhance survival rates especially in the more advanced and severely-affected COVID-19 patients ( Chakraborty et al., 2020 ; Narożna and Rubiś, 2021 ; Okuyan and Begen, 2021 ; Schultz et al., 2021 ; Choe et al., 2022 ; Kucher et al., 2022 ).…”

“…Regarding this latter function, recent evidence further indicates that miRNAs play an important role in the complex interplay between viruses (containing both DNA and RNA genomes) and host cell genetics ( Hill et al., 2009 ; Mishra et al., 2020 ; Wicik et al., 2020 ; Narożna and Rubiś, 2021 ; Schultz et al., 2021 ; Siniscalchi et al., 2021 ; Zhao et al., 2021 ). An interesting relevant example is that the NF-kB-sensitive Homo sapiens microRNA-146a (hsa-miRNA-146a-5p) is significantly over-expressed within brain and CNS tissues of progressive and often lethal viral-mediated neurological syndromes associated with age and advancing inflammatory neurodegeneration, and these include ~18 different viral-induced encephalopathies involving both single- and double-stranded RNA and/or DNA viruses ( Pogue and Lukiw, 2021 ; Kucher et al, 2022 ). Despite huge research efforts, whether this represents part of the host’s adaptive immunity, innate-immune response or a mechanism to enable the invading virus a successful infection is currently not well understood ( Jones et al., 2021 ; Narożna and Rubiz 2021 ; Pogue and Lukiw, 2021 ).…”

“… SARS-CoV-2 or other single-stranded viral RNAs (ssvRNAs) may be recognized (via base-pair complementarity) and degraded by miRNA-mediated interactions within the cell cytoplasm; there are multiple types of evidence that at least 25 miRNAs have potential to target SARS-CoV-2 and other ssvRNA sequences ( Arisan et al., 2020 ; Hosseini Rad Sm and McLellan, 2020 ; Jafarinejad-Farsangi et al., 2020 ; Kucher et al., 2022 ); the natural functions of most of the miRNAs listed in Table 1 are not known (see manuscript text); interestingly one recent in silico study using miRBase, MiRanda and Gene Set Enrichment Analysis (GSEA) software provided evidence: (i) that the miRNA-29 family had the most binding sites (N=11) on the SARS-CoV-2 ssvRNA genome ( Jafarinejad-Farsangi et al., 2020 ); and (ii) using RNA-sequencing analysis, RNAhybrid 2.2 and MirTarget analytical programs between 857 and 2654 miRNAs have potential to interact with the ~29,903 nt SARS-CoV-2 ssvRNA genome (SARS-CoV-2 isolate Wuhan-Hu-1, National Center for Biological Information (NCBI) GenBank Accession No. NC_045512.2 ; last accessed 30 April 2022; Ke et al., 2020 ; Sah et al., 2020 ; Wu et al., 2020 ; Mousavizadeh and Ghasemi, 2021 ; Kucher et al., 2022 ). The SARS-CoV-2 ssvRNA genome thereby presents a potential target for naturally occurring human miRNA-mediated ssvRNA inactivation and neutralization; this may play an under-appreciated role in natural host immunity and the high variability in the innate-immune and pathophysiological response of different human individuals to SARS-CoV-2 and their overall susceptibility to ssvRNA-mediated viral infections that include COVID-19.…”

SARS-CoV-2 Neuroinvasion, Inflammatory Neurodegeneration and Alzheimer's Disease

“…Small non-coding RNAs (sncRNAs) known as microRNAs (miRNAs) have emerged as extremely informative diagnostic, prognostic and therapeutic biomarkers in inflammatory and infectious disease including incapacitating viral infections of the brain and AD. For example, increases in the proinflammatory NF-kB (p50/p65)-inducible miRNA-146a and miRNA-155, significantly up-regulated in AD-and prionaffected brain and CNS and implicated in pathological disruption of the innate-immune system, altered microglial-regulated wasteproduct clearance and complement factor H (CFH)-mediated complement activation, most often accompanies the viral-, bacterial-and other microbial-mediated infections of all brain cells and tissues examined to date (Slota and Booth, 2019;Li et al, 2021;Pogue and Lukiw, 2021;Azhar et al, 2022;Choe et al, 2022;Kucher et al, 2022;Maranini et al, 2022;Pogue et al, 2022). Importantly, the abundance, speciation and complexity of miRNA populations varies considerably in the individual human host and because miRNAs can target and inactivate ssRNA viruses such as H1N1/H3N2, Zika virus and SARS-CoV-2 may help to explain individual heterogeneity in the susceptibility to systemic attack and infection by human ssRNA viruses (Azhar et al, 2022;Hill and Lukiw, 2022;Kucher et al, 2022).…”