Why is the COVID-19 virus lethal, whereas many different coronaviruses are pretty innocuous and simply trigger colds?
A staff of University of Alabama at Birmingham and Polish researchers suggest a solution—the COVID-19 virus acts as a microRNA “sponge.” This motion modulates host microRNA ranges in ways in which assist viral replication and stymies the host immune response.
This testable speculation outcomes from evaluation of present literature and a bioinformatic research of the COVID-19 virus and 6 different coronaviruses. It is printed as a perspective in the American Journal of Physiology-Lung Cellular and Molecular Physiology.
Human microRNAs, or miRNAs, are brief, non-coding RNAs with about 22 bases. They act to manage gene expression by their complementary pairing with specific messenger RNAs of the cell. That pairing silences the messenger RNA, stopping it from being translated right into a protein. Thus, miRNAs are a fine-tuned controller of cell metabolism or the cell’s response to emphasize and adversarial challenges, like an infection by a virus.
The miRNAs are solely about 0.01 % of complete human cell and tissue RNA, whereas replicating viral RNA of a virus like the COVID-19 virus might attain 50 % of the complete mobile RNA. So, the UAB and Polish researchers say, if the COVID-19 virus has binding websites for specific miRNAs—and these websites are completely different from the binding websites for miRNAs discovered on coronaviruses that trigger colds—the extra pathogenic COVID-19 virus might selectively sponge up sure miRNAs to dysregulate the cell in ways in which make it a harmful human coronavirus.
The sponge concept will not be novel. Viral RNA sponges have been proven able to eradicating host miRNA by the Epstein-Barr virus, and sponge exercise has additionally been proven for the herpes and hepatitis C viruses.
There had been two human coronaviruses previous to the COVID-19 virus—whose formal identify is SARS-CoV-2—that foreshadowed the devastating penalties of the COVID-19 virus. The first was the extreme acute respiratory coronavirus, or SARS virus, in 2002; the second was the Middle East respiratory syndrome coronavirus, or MERS virus, in 2012. Neither had the excessive infectivity of the COVID-19 virus; however each had been harmful, inflicting 774 and 866 deaths, respectively, in line with the National Institutes of Health.
In the current research, the researchers used computer-aided bioinformatic evaluation to search out potential miRNA goal websites for 896 mature human miRNA sequences on seven completely different coronavirus genomes. These genomes included the three pathogenic coronaviruses—the SARS, MERS and COVID-19 viruses—and 4 non-pathogenic coronaviruses.
The researchers discovered that the variety of goal websites was elevated in the pathogenic viruses in comparison with the non-pathogenic strains. Furthermore, they discovered that pathogenic human coronaviruses attracted units of miRNAs that differ from the non-pathogenic human coronaviruses. In specific, a set of 28 miRNAs had been distinctive for the COVID-19 virus; the SARS and MERS viruses had their very own distinctive units of 21 and 24 miRNAs, respectively.
Focusing on the 28 distinctive miRNAs for the COVID-19 virus, the researchers discovered that the majority of those miRNAs are properly expressed in bronchial epithelial cells, and their dysregulation has been reported in human lung pathologies that embody lung cancers, power obstructive pulmonary illness, cystic fibrosis and tuberculosis. Furthermore, a lot of the miRNAs have been proposed to behave as tumor suppressors that concentrate on the pathways for programmed cell demise, or apoptosis, which can be presupposed to make a cell kill itself when contaminated, mutated or confused in different methods. Reduction of these miRNAs has been related to poor most cancers prognosis.
“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,” the researchers mentioned.
The authors gave an in depth clarification of how the virus replicates inside an infected cell, together with how the cell assists protein folding and the way the virus begins meeting in the cell’s endoplasmic reticulum and Golgi system. They additionally described a lot of the mobile proteins concerned in these steps. This viral replication is thought to supply stress and may provoke an unfolded protein response that causes a cell to endure programmed demise.
“Taken together,” the researchers mentioned, “the viral strategies to increase the endoplasmic reticulum membranes and endoplasmic reticulum folding capacity and block unfolded protein response-associated translational attenuation, inflammatory responses and apoptosis are critical components for virus production.”
The authors then confirmed, by citing literature, that 9 of the specific mobile miRNAs that doubtlessly are sponged by the COVID-19 virus may assist obtain these viral wants.
“The host miRNAs potentially controlled by the pathogenic human coronaviruses may be the key to gaining control over a very limited and specific set of miRNAs targets,” they mentioned. The researchers used computer-assisted gene ontology applications to search out the genes and mobile pathways affected by the pathogenic human coronaviruses, and by the COVID-19 virus specifically.
The pathways they discovered “further supports 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.”
“Our hypothesis will require validations,” they mentioned, “starting with the assessment of these miRNA levels in infected tissues and ending with restoring the host miRNA balance with miRNA analogs. Furthermore, completely understanding how viruses take advantage of the endoplasmic reticulum and unfolded protein response pathway may also lead to the novel therapeutic strategies.”
This speculation by the UAB and Polish researchers, who all contributed equally to the paper, might clarify another organic oddities of the COVID-19 virus.
One is the various susceptibilities to an infection seen amongst sufferers, together with a extra extreme morbidity and mortality for older sufferers. There could also be particular person variations amongst affected person miRNA profiles, they mentioned, and one “recent study has suggested that COVID-19 virulence in aged patients may be due to a lower abundance of miRNAs, and this may be a contributing factor in disease severity.”
Another organic query is how the virus co-exists in its regular animal supply—bats. “Notably,” the researchers mentioned, “a recent study proposed that bats, considered as host of origin for the COVID-19 virus, have tolerance to potentially deadly viruses because of specific miRNAs.”
Rafal Bartoszewski et al, SARS-CoV-2 might regulate mobile responses by way of depletion of specific host miRNAs, American Journal of Physiology-Lung Cellular and Molecular Physiology (2020). DOI: 10.1152/ajplung.00252.2020
University of Alabama at Birmingham
Is the COVID-19 virus pathogenic because it depletes specific host microRNAs? (2020, August 14)
retrieved 14 August 2020
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