A team of researchers, including scientists of the HSE Faculty of Biology and Biotechnology, have analysed the evolutionary path of the coronavirus from the Wuhan variant to Omicron. Their findings indicate that many genomic mutations in SARS-CoV-2 are shaped by processes occurring in the intestines and lungs, where the virus acquires the ability to evade the inhibitory effects of microRNA molecules. The study findings have been published in the Journal of Medical Virology.
Upon entering the human body, a virus infiltrates cells and initiates a replication process, generating numerous copies of itself to facilitate the infection of additional cells. Random errors—mutations—can occur during replication. Those mutations which somehow enhance the virus's properties, such as enabling it to evade the host's immune response or facilitating faster transmission within the population, can become fixed and lead to the emergence of a new strain.
SARS-CoV-2 can serve as an example of this phenomenon. There are thousands of documented genomic mutations of the coronavirus, encompassing over 10 distinct variants, not including additional lineages. The GISAID international database contains more than 14 million SARS-CoV-2 sequences, making it possible to track the virus’s evolution with unprecedented precision. It has been demonstrated, for instance, that coronavirus mutations can arise in response to pressure from antibodies targeting the viral spike protein's receptor-binding domain, which is the initial point of contact with human cells. Yet this is just one of several mechanisms driving the evolution of the virus.
According to HSE Faculty of Biology and Biotechnology researchers Anton Zhiyanov, Maxim Shkurnikov, Ashot Nersisyan, and Alexander Tonevitsky, the virus can change under the influence of microRNAs. These are short non-coding RNA sequences, comprising only 22 nucleotides, which play a role in regulating protein levels within human tissues. MicroRNAs bind to the regions of RNA which are reverse-complementary to their own sequence, subsequently inhibiting the RNA’s transition into protein. The same process occurs in cells affected by the virus. MicroRNA molecules can adhere to the viral RNAs, impeding their subsequent replication.
Having analysed the genomic sequences of SARS-CoV-2 documented between December 2019 and the present, the researchers discovered that microRNAs in the intestines and lungs eventually stopped recognising the virus. Apparently, the substitutions that occurred in the viral genome in the course of its evolution disrupted the complementarity of RNA regions through which microRNAs could identify the virus, leading to the emergence of the more contagious and resilient Omicron strain.
The virus enters the human body through the epithelium in the lungs and intestines, so our main focus was on these organs. However, we also examined other organs such as the brain, liver, and bladder, as controls. But only within the intestines and lungs did we observe a significant drop in the number of regions where microRNAs could bind to the virus. The loss of these regions was particularly prominent in the Omicron variant.
Interestingly, while COVID-19 is commonly associated with respiratory issues, our findings indicate that the virus's priority lies in evading the immune response within the intestines, where the most pronounced reduction in binding regions has been observed. The virus can persist in the intestines for an extended period, causing a sluggish inflammatory process referred to as ‘long COVID’. Possibly during this stage, the advantageous mutations for the virus are fixed, allowing it to re-emerge in the population with renewed strength.