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MicroRNA, a double-edged sword: role in viral infections and autoimmune diseases

Read time: 4 mins
19 Jan 2022
MicroRNA, a double-edged sword: role in viral infections and autoimmune diseases

Our immune system has the necessary ammunition needed to fight against microbial infections. All it needs, however, is a trigger to activate it. When viruses invade us, our body fights them with many genes that produce chemicals called interferons and cytokines. But what regulates these genes, and when should they be expressed?

Scientists from the Indian Institute of Science Education and Research (IISER), Bhopal, have discovered one such molecule that sets off a trigger to initiate the arsenal against invading viral agents. The triggering agent was found to be a short ribonucleic acid (RNA) molecule called miR-30e. miRNAs are much shorter than normal RNAs (molecules that carry messages from DNA). The study also suggests that targeting the miRNA could lead to treatment options for autoimmune diseases such as systemic lupus erythematosus, commonly known as Lupus. The research was published in iScience, from Cell Press and funded by IISER Bhopal, Indian Council for Medical Research (ICMR), and Hokkaido University, Japan.

The genes that trigger a reaction to infections need not be active always but have to switch on only when the infectious agent attacks. To keep a checkpoint and fine-tune this process, another set of genes called negative regulators come into play, which suppresses the expression of the fighter genes. However, these negative regulators need to be suppressed when a virus invades, thus allowing the immune genes to produce the desired type of interferons and cytokines.

So what regulates the regulators? A small RNA molecule called microRNA-30e (or miR-30e for short) acts as the master regulator. The usual job of these miRNAs is to regulate the expression of other genes.

miRNAs have a peculiar way of controlling the expression of other genes. Usually, genes are expressed by copying information from DNA to a messenger RNA (mRNA) which is then translated into proteins. miRNAs activate after the genes are copied into messenger RNA and then bind to the mRNA (by a process called complementary binding or complementary base pairing). The targeted mRNA is either destroyed later by other enzymes or suppressed from producing proteins.

miR-30e regulates the immune response genes similarly when a virus infects. Researchers got the first clue about miRNA-30e’s role while looking into virus-infected cells. They found the infected cells were teeming with these micro RNA molecules. “When we observed the levels of microRNAs, miR-30e was produced at higher quantities in infected cells compared to normal cells,” says Ms Richa Mishra, the first author of this research paper.

Researchers maintain a database for DNA, RNA, and microRNA sequences generally. Also, a special database is maintained for gene sequences expressed in virus-infected cells. When researchers scanned such a database of different virus infected cells, miR-30e popped up consistently, showing that miR-30e is always found in virally infected cells.

Having zeroed in on miR-30e as an important player for viral infection response, the researchers next engineered cultured cells to produce more copies of this miRNA. They then infected the cultured cells with different types of viruses. “ We noticed that introduction of the miR30e reduced the viral load in the infected cells as compared to non-infected cells. Therefore, our initial results of increased immune responses in miR-30e treated cells upon different virus infections respectively, eventually connected with the decreased virus infection,” says Ms Mishra. miR-30e, therefore, was playing a pivotal role in mounting an immune response to viral infection. And could be considered as a therapeutic candidate against virus infections.

The team further investigated the exact role of the molecule. miRNA-30e was found to suppress the negative regulators of immune genes, thereby allowing the immune genes to produce interferons and cytokines to fight against the virus infection. Thus, this particular microRNA was at the central position, initiating and regulating immune response like a ringmaster in a circus.

However, the process is not foolproof if the miR-30e production and activity go unchecked.  Prolonged production of miRNA can lead to a state where immune genes are active all the time. Such a situation may result in the immune genes attacking healthy tissues in the body, causing autoimmune diseases.  When the researchers experimented on disease-induced mice, that is, with an autoimmune disease mouse model system and also in the patient samples, they found an overproduction of miR-30e in the cells of both mice and human patients.

Therefore, the researchers found that while miR-30e is sequestering negative regulators and enhancing immunity, the molecule levels in the cells were crucial in the case of autoimmune diseases like Lupus (SLE).

“So we proposed a chemical or synthetic inhibitor of miR-30e called ‘antagomir’ which has a complex chemistry behind its synthesis as a potential diagnostic candidate for Lupus,” says Ms Mishra.

When researchers injected antagomir into a diseased mouse, it significantly reduced the miR-30e abundance, controlling the excessive activity of the immunity genes – thereby predicting the importance of miR-30e in the diagnosis of autoimmune disease.

This study indicates that exploiting the immune regulation through miR-30e could be a master therapeutic and prognostic option: to combat viral infections and some autoimmune diseases.

This article has been run past the researchers, whose work is covered, to ensure accuracy.