In somatic cells, microRNAs (miRNAs) bind to the genomes of RNA viruses and influence their translation and replication. Here we demonstrate that a significant number of miRNA binding sites locate in the NSP4 region of the SARS-CoV-2 genome, and the intestinal human miRNAs exert evolutionary pressure on this region. Notably, in infected cells, NSP4 promotes the formation of double-membrane vesicles, which serve as the scaffolds for replication-transcriptional complexes and protect viral RNA from intracellular destruction. In three years of selection, the loss of many miRNA binding sites, in particular, those within the NSP4, has shaped the SARS-CoV-2 genomes to promote the descendants of the BA.2 variants as the dominant strains and define current momentum of the pandemics.

In somatic cells, microRNAs (miRNAs) bind to the genomes of RNA viruses and influence their translation and replication. Here we demonstrate that a significant number of miRNA binding sites locate in the NSP4 region of the SARS-CoV-2 genome, and the intestinal human miRNAs exert evolutionary pressure on this region. Notably, in infected cells, NSP4 promotes the formation of double-membrane vesicles, which serve as the scaffolds for replication-transcriptional complexes and protect viral RNA from intracellular destruction. In three years of selection, the loss of many miRNA binding sites, in particular, those within the NSP4, has shaped the SARS-CoV-2 genomes to promote the descendants of the BA.2 variants as the dominant strains that define current momentum of the pandemics. Findings highlight the possibility that intestinal tissue may significantly impact evolution of the SARS-CoV-2 genome and may play a pivotal role in the long COVID.

In somatic cells, microRNAs (miRNAs) bind to the genomes of RNA viruses and influence their translation and replication. In London and Berlin samples represented in GISAID database, we traced severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) lineages and divided these sequenced in two groups, “Ancestral variants” and “Omicrons,” and analyzed them through the prism of the tissue‐specific binding between host miRNAs and viral messenger RNAs. We demonstrate a significant number of miRNA‐binding sites in the NSP4 region of the SARS‐CoV‐2 genome, with evidence of evolutionary pressure within this region exerted by human intestinal miRNAs. Notably, in infected cells, NSP4 promotes the formation of double‐membrane vesicles, which serve as the scaffolds for replication‐transcriptional complexes and protect viral RNA from intracellular destruction. In 3 years of selection, the loss of many miRNA‐binding sites in general and those within the NSP4 in particular has shaped the SARS‐CoV‐2 genomes. With that, the descendants of the BA.2 variants were promoted as dominant strains, which define current momentum of the pandemics.