microRNA‐146a and ‐155, upregulated by periodontitis and type 2 diabetes in oral fluids, are predicted to regulate SARS‐CoV‐2 oral receptor genes

Abstract

Background: Type 2 diabetes and periodontitis predispose to a higher risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recent studies show upregulation of innate immuno-regulatory microRNA-146a and -155 in oral fluids of patients with type 2 diabetes as well as of patients with periodontitis. The aim was to investigate whether upregulation of these microRNAs may relate to patient susceptibility to the infection via modulation of SARS-CoV-2 cellular entry factors expression. Methods: Due to limited experimental feasibility and health risks in Coronavirus Disease 2019, bioinformatic analyses combining with system biology were used as initial investigation of interaction between microRNA-146 and -155 and genes encoding SARS-CoV-2 entry factors. Results: SARS-CoV-2 cellular entry factors are expressed in salivary glands and masticatory mucosa (tongue) at different expression levels, comparable with those measured in lungs and tonsil. MicroRNA-146 and -155 are widely involved in the regulation of SARS-CoV-2 oral cellular entry factors and may enhance expression of ACE2 and modulate genes involved in host immunity.Conclusions: Diabetes-and periodontitis-induced increase in microRNA-146a and -155 in oral cavity is predicted to upregulate angiotensin-converting enzyme 2 expression, essential SARS-CoV-2 entry receptors, and modulate host antiviral response. As it could suggest increased infectivity of diabetes and periodontitis patients, additional protective measures for periodontists are recommended.

Periodontal Diseases and COVID-19: A Scoping Review

“…Among the 22 studies related to this topic, 15 were nonexperimental studies 12,[15][16][17][18][19]21,[23][24][25]27,28,30,32,35 ; there were seven experimental reports. 13,14,26,31,33,34,36 For 16, the type of article was clearly indicated; seven were original articles, 13,14,26,31,33,34,36 four were letters to the editor, 17,18,25,30 four were revi ews, 24,28,32,35 and one was a "commentary." 27 Among the six for which this was not clearly indicated, we considered that five were short reports 12,15,16,19,21 -one of which reported an ongoing clinical trial, 16 and one was a review.…”

“…27 Among the six for which this was not clearly indicated, we considered that five were short reports 12,15,16,19,21 -one of which reported an ongoing clinical trial, 16 and one was a review. 23 The information relating to the topic found in the papers was the SARS-CoV-2 entry mechanism, [12][13][14]16,18,21,[24][25][26][27][28][30][31][32]36 the mechanism of how periodontitis might influence the entry of SARS-CoV-2 into cells or might worsen COVID-19, [15][16][17][18][19]21,[23][24][25][26][27][28]30,[32][33][34][35][36] and antiviral targets to treat COVID-19 (►Table 1). 14,18,24,27…”

“…13,14,16,18,21,[24][25][26][27][28]30,32,36 The latter is present in several tissues including lungs, nasopharyngeal mucosa, salivary glands, and oral mucosa. 13,14,16,18,24,27,30,36 Within the oral mucosa, ACE-2 is mainly expressed not only by epithelial cells but also by fibroblasts, 16 T cells, and B cells; it is not only detected in the lip, tongue, and buccal mucosa but also in the gingival (stratified squamous epithelium) and palatal tissue. 13,14,18,26 One of the hypotheses is that furin, cathepsin, and TMPRSS2 proteases allow the entry of SARS-CoV-2 into cells.…”

Presence of SARS-CoV-2 and Its Entry Factors in Oral Tissues and Cells: A Systematic Review

“…For example, Roganović reports that it is possible that the presence of diabetes and periodontitis in patients infected by SARS-CoV-2 causes an increase of two microRNAs (-146a and -155) which in turn causes a greater expression of the ACE2 receptor. This seems to favor the mechanisms of SARS-CoV-2 infections in periodontal tissues; however, this study was carried out through a bioinformatics analysis, so clinical or in vitro studies are needed to confirm these findings [ 49 ]. Marouf et al determined that the presence of periodontitis in SARS-CoV-2 positive patients is associated with a greater severity of the disease and an increased risk of death [ 50 ].…”

microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD)

“…Recent evidence has indicated that, in general, endogenous human miRNAs (small, single-stranded~22 nt RNAs, such as miRNA-146a) might have a significant antiviral role and hence may be useful to the host in an innate-immune defense by targeting the single-stranded viral ribonucleic acid (ssvRNA) genomes of several different neurotropic viruses, such as SARS-CoV-2, and function to downregulate or modulate their expression [77,78]. To this end, and to quote just one recent example, RNA sequencing and other analytical genetics in RNA-based sequence studies have shown that at least~160 of the~2650 of the 18-22 nt naturally occurring human single-stranded miRNAs have per-fect complementarity within the miRNA-mRNA 'seed region' of the SARS-CoV-2 ssvRNA genome, and these include the unique hsa-miRNA-146a ribonucleotide sequence and those of other related microRNA gene families [47,73,[79][80][81]. Interestingly, the apparent lack of nucleic acids detectable within the prion particle indicates that some yet poorly understood pathological mechanism is responsible for the prion-mediated upregulation of miRNA-146a when neurons are confronted with infection by these neurological-disease inducing sialoglycoproteins [16,53,60,75,82,83].…”