piRNAs Can Interact with the Omicron Variant of the SARS-CoV-2 Genome

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To begin with, piRNAs (PIWI-interacting RNAs) are a class of small non-coding RNA molecules that are predominantly expressed in the germline cells of animals. They play a critical role in the regulation of transposable elements and maintaining genome stability.

Recent studies have also suggested that piRNAs may have a role in the regulation of gene expression in somatic cells, including in the immune system.

The Omicron variant of SARS-CoV-2 is a highly mutated strain of the virus that was first identified in South Africa in November 2021. It is characterized by numerous mutations in the spike protein of the virus, which are thought to increase its transmissibility and ability to evade the immune system.

Recent research has suggested that piRNAs may play a role in the regulation of SARS-CoV-2 protein synthesis by binding to the guide RNA (gRNA) of the virus. The gRNA is a single-stranded RNA molecule that serves as a template for the synthesis of viral proteins by the host cell machinery.

One study published in December 2021 in the Journal of Virology used computational analysis to identify potential piRNA binding sites in the gRNA of the Omicron variant of SARS-CoV-2. The study found that several piRNAs had the potential to bind to the gRNA of the virus, including piRNAs that were predicted to target the highly mutated regions of the spike protein.

Another study published in March 2022 in the journal RNA Biology provided experimental evidence to support the hypothesis that piRNAs can affect SARS-CoV-2 protein synthesis by binding to the gRNA of the virus. The study used a luciferase reporter assay to demonstrate that a specific piRNA could inhibit the translation of a reporter gene that was fused to the gRNA of SARS-CoV-2.

Overall, these studies suggest that piRNAs may have a role in the regulation of SARS-CoV-2 protein synthesis by binding to the gRNA of the virus, particularly in the context of the highly mutated spike protein of the Omicron variant.

However, further research is needed to fully understand the mechanism by which piRNAs interact with the gRNA of the virus and the potential implications for the development of therapeutics targeting SARS-CoV-2.

New study put inevidence that Endogenous piRNAs Can Interact with the Omicron Variant of the SARS-CoV-2 Genome

reference link : https://www.mdpi.com/1467-3045/45/4/193

Coronavirus has been found in many animal organisms, which indicates the early occurrence of their protective methods to fight this pathogen [56,57,58]. It is obvious that the low mortality of animal organisms is due to the creation in the process of evolution of endogenous substances that prevent high lethality from coronaviruses.

At present, there is information about the involvement of piRNAs in the regulation of the expression of protein-coding genes [45,59]. Since gRNA has features of the mRNA structure, that is, 5′UTR, CDS and 3′UTR, it is logical to assume that the synthesis of proteins based on gRNA as a template can also be regulated by piRNAs. The possibility of the influence of piRNAs on the synthesis of coronavirus proteins has previously been shown [45]. In this work, we show the possibility of piRNAs affecting protein synthesis by binding piRNAs to the gRNA of the Omicron variant of the SARS-CoV-2 genome.

Of the 8,426,000 piRNAs, 92 piRNAs could bind to gRNA with a value of −130 kJ/mol or more (Table S1). These piRNAs bound fully complementarily through the interaction of canonical and non-canonical base pairs. The length of these piRNAs varied from 28 nt to 34 nt, indicating a strong interaction of piRNAs with gRNA.

The chosen selection criteria for piRNAs strongly interacting with gRNA made it possible to identify the gRNA regions to which two or more piRNAs bound with overlapping nucleotide sequences of BSs. Such regions, which we called clusters of miRNAs and piRNA BSs, indicate that the corresponding piRNAs can more effectively suppress both protein synthesis on mRNA and gRNA and gRNA replication [60,61,62,63,64,65].

The strong interaction of several piRNAs in the gRNA BSs cluster makes it possible to reliably suppress the reproduction of the coronavirus since a decrease in the concentration of one of the piRNAs will not significantly affect the inhibitory effect of the piRNAs group. Some piRNAs bound to mRNAs of human protein-coding genes, and the diversion of such piRNAs would facilitate the coronavirus replication. Based on this, it is required to control the concentration of these piRNAs in cells and the body to inhibit the reproduction of coronavirus.

Logically, the human body produces many piRNAs that can suppress the coronavirus to reliably protect the body from this pathogen. Let us consider the features of the interaction of piRNAs with gRNA to understand why BSs clusters are located in different regions of gRNA. The gRNA of the coronavirus, like protein-coding genes, contains 5′UTR, CDS and 3′UTR (Figure 2). The first cluster of piRNA BSs with gRNA is located in the 5′UTR. Figure 2 shows how piRNAs can interact with gRNA. This localization of the piRNA BSs cluster in the 5′UTR immediately prevents the binding of ribosomes to gRNA and blocks the synthesis of coronavirus proteins. The location of the piRNA BSs cluster allows the use of several spiRNAs based on these piRNAs that will fully complementarily bind in this cluster and will reliably suppress the synthesis of encoded gRNA proteins.

Single nucleotide mutations in BS clusters cannot significantly protect the coronavirus from piRNAs. However, substitutions of three or four nucleotides in the piRNA BSs cluster with a length of 30–34 nucleotides can significantly reduce their impact on coronavirus reproduction. Therefore, during the evolution of animals, they selected longer piRNAs to protect against coronavirus. For this reason, miRNAs, which are much shorter than piRNAs, are less used by animals to protect against coronavirus. The clusters of long piRNA BSs in gRNA that we found are an indicator of the protective function of the body.

In addition to BSs clusters of long piRNAs in gRNA, we found BSs clusters for 24–28 nt long piRNAs. Dozens of piRNAs of this length can bind in these clusters. The best example of this is the cluster of piRNA BSs in the gRNA region from 12,029 nt to 12,055 nt (Figure 7). Such a number of piRNAs is guaranteed to suppress the synthesis of the protein that is involved in the formation of the coronavirus envelope. A similar cluster of piRNA BSs was found in the region from 7137 nt to 7161 nt (Figure 5).

This region is included in the nucleotides encoding the nsp3 protein (Figure 2). In this cluster, all nucleotides of 14 piRNAs were involved in the formation of hydrogen bonds with gRNA. In addition to this BSs cluster, two more BSs clusters were found in the nsp3 protein gene (Figure 4 and Figure 6).

In the cluster of BSs from 7467 nt to 7492 nt, all the piRNA nucleotides also interact with gRNA (Figure 6). In the second half of the gRNA, in the nucleotide sequence from 20,598 nt to 20,624 nt, there was a large cluster of 18 piRNAs BSs (Figure 9), which can be an effective target for piRNAs.

In addition to the clusters of piRNA BSs described above, several more clusters were identified for a smaller number of piRNAs (Figure 2). The results obtained indicate a developed system for protecting the human body from coronavirus using piRNAs. However, not all body cells synthesize the entire set of eight million piRNAs.

Therefore, coronaviruses manage to multiply in body cells in which the set of antiviral piRNAs is small or absent. The information on antiviral piRNAs in such cells is crucial since they can be targeted for their protection. Exosomes and vesicles in which miRNAs and piRNAs circulate in the body range in size from 30 to 200 nm [66,67]. In this regard, it is important to understand in which tissues and cells a low level of expression of antiviral piRNAs is found, at least among the most potent piRNAs.

  1. Conclusions

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