A team of researchers from the University of Alabama at Birmingham and various institutions in Poland proposes that the SARS-CoV-2 virus acts as a microRNA “sponge” to reduce microRNA levels in ways that assist viral replication and block the host immune response.

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New research suggests that SARS-CoV-2 may be more dangerous than other coronaviruses because it reduces specific microRNAs.

The perspective appears in the American Journal of Physiology-Lung Cellular and Molecular Physiology.

Coronaviruses (CoVs) are single-stranded RNA viruses that experts originally considered to be relatively mild. They include the viruses that cause the common cold.

However, researchers have stopped thinking of these viruses as mild after the outbreaks of severe acute respiratory coronavirus (SARS-CoV) in 2002, Middle East respiratory syndrome (MERS-CoV) in 2012, and the current global COVID-19 pandemic, for which the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible.

Neither the SARS nor the MERS virus had the high infectivity of the novel coronavirus, but both were dangerous, resulting in 774 and 866 deaths, respectively. Although there are similarities in their RNA sequences, they differ significantly in their methods of infection.

Currently, there is no vaccine available for SARS-CoV-2. Research has focused on understanding virus pathogenicity and, importantly, on restoring and enhancing patients’ immunity. Researchers are now considering innovative approaches, such as the use of human microRNAs (miRNAs).

MiRNAs are vital players in the body’s immune defense against viruses. They are short, noncoding RNAs that regulate gene expression through their complementary pairing with specific messenger RNAs of the cell.

By latching onto and cutting the viral RNA, miRNAs control the cell’s response to create an antiviral effect. However, viruses also have the capability to maneuver the host miRNA networks according to their own rules.

When microRNAs are inhibited or low in abundance, the virus can more freely replicate, avoid immune responses, and increase disease severity.

In the current study, the researchers aimed to answer why these viruses are so different from the typically harmless cold viruses.

They hypothesized that the virus that causes COVID-19 has binding sites for select miRNAs that are different than the binding sites for miRNAs on coronaviruses that cause the common cold.

The more pathogenic SARS-CoV-2 virus may specifically serve as a miRNA sponge, reducing cellular miRNA levels to make it a more hazardous human coronavirus.

By analyzing the current literature and using computer-aided bioinformatic techniques, the team evaluated the potential miRNA interactions with the SARS-CoV-2 genome and looked for possible miRNA target sites for 896 human miRNA sequences on seven different coronavirus genomes.

The genomes included those of the three pathogenic coronaviruses — SARS-CoV-2, MERS-CoV, and SARS-CoV — and four nonpathogenic coronaviruses.

The analysis revealed that the number of microRNA target sites was higher in the pathogenic viruses than in the nonpathogenic viruses.

Additionally, the sets of microRNAs that the pathogenic coronaviruses targeted were different than those that the nonpathogenic coronaviruses targeted.

Specifically, the researchers discovered a set of 28 miRNAs that are unique to SARS-CoV-2, as well as sets of another 21 and 24 miRNAs that are unique to SARS-CoV and MERS-CoV, respectively.

Further analysis of the 28 unique miRNAs for COVID-19 revealed that most of these miRNAs are significantly expressed in bronchial epithelial cells. Researchers have studied their dysregulation in human lung diseases, such as tuberculosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and lung cancer.

As an immune defense mechanism, these miRNAs are programmed to make cells kill themselves if they become mutated, infected, or stressed.

Furthermore, nine of these microRNAs that SARS-CoV-2 potentially “sponges” may help the virus achieve viral loads. “Hence, the COVID-19 virus — by its potential reduction of the host’s miRNA pool — may promote infected cell survival and thus continuity of its replication cycle,” explain the authors.

The authors went on to detail how the virus replicates inside an infected cell, the molecular pathways involved, and the cellular responses to it.

The researchers’ findings “further [support] the hypothesis that pathogenic human coronaviruses — including the COVID-19 virus — utilize the host miRNAs to adjust cellular processes in order to facilitate their viral protein production.”

A limitation of the study is that the team did not factor in the individual differences in people’s miRNA profiles, but susceptibility to infection varies among individuals. For example, disease severity and death rates have been higher among older adults.

A recent study suggests that in older patients, COVID-19 virulence may be due to a lower quantity of miRNAs, indicating that they play a role in disease severity. “Understanding these types of differences in patients is important for developing personalized antiviral therapies,” note the study authors.

The results of this study have provided a potential new strategy for the treatment of COVID-19. Synthetic miRNAs may be able to aid the restoration of key miRNA levels, helping them combat COVID-19.

The researchers acknowledge that their “hypothesis will require validations, starting with the assessment of these miRNA levels in infected tissues and ending with restoring the host miRNA balance with miRNA analogs.”

“Furthermore,” they add, “completely understanding how viruses take advantage of the [endoplasmic reticulum] and [unfolded protein response] pathway may also lead to the novel therapeutic strategies.”

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