SARS-CoV-2 and COVID-19
The new human coronavirus SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic that has infected millions of people and caused ~4 million deaths at the time of writing this article. While some COVID-19 patients remain asymptomatic or have mild infection, others develop severe organ damage or succumb to the disease.
Current treatment options for SARS-CoV-2 are limited and many have not generated sufficient evidence on efficacy or safety for treating COVID-19. While effective vaccines have been developed, there is still a crucial need to develop effective antivirals, especially in the context of emerging SARS-CoV-2 variants and strains with resistance to the vaccines.
A novel SARS-CoV-2 antiviral strategy could come from the use of drugs that either mimic or inhibit specific types of microRNAs (miRNAs). Our own cells are able to generate different antiviral strategies, with RNA interference being an effective approach. RNA interference is mediated by a group of RNA molecules known as miRNAs. Unlike messenger RNA (mRNA), which codes for specific proteins, miRNA does not code for proteins. Instead, miRNA binds to complementary mRNA sequences to block their function, cause their degradation and thus prevent protein expression.
While our own cells can make use of miRNAs to counteract viral infections, viruses can also induce alterations in host miRNA expression to amplify specific microenvironments that facilitate the viral life cycle. For example, the Epstein–Barr virus is able to upregulate the levels of a specific miRNA (miR-155) in infected B lymphocytes, which consequently decreases the production of a protein that is essential for cytokine production and cell survival. Consequently, by upregulating miR-155, the Epstein–Barr virus prevents effective communication between infected B lymphocytes and other immune cells, suppressing immune responses to viral infection.
miRNAs as antiviral targets
By making host cells more prone to viral infection, miRNAs serve an important role in regulating viral infections, highlighting an opportunity to develop novel antiviral therapeutics with the potential to interfere with such pathways.
There are two approaches for developing miRNA-based therapeutics (Figure 1). The first one involves the development of miRNA inhibitors to increase the expression of proteins that are downregulated during viral infections. Such proteins may have either direct antiviral functions or anti-inflammatory effects. Therefore, increasing their expression through miRNA inhibition may not only reduce viral infectivity, but also reduce inflammation and organ damage.
The second strategy consists of deploying miRNA mimics to decrease the production of proteins that favour viral infectivity or inflammatory pathways that mediate organ damage.
Figure 1. Potential therapeutic applications of miRNAs. Through miRNA suppression (left side), mRNA expression and translation that is downregulated during viral infections can be restored. Whereas, through miRNA enhancement (right side), mRNA expression and translation that is upregulated during viral infections can be prevented.
miRNA therapeutics against COVID-19
The initial step prior to developing miRNA therapeutics against COVID-19 relies on the identification of relevant miRNAs modulated during SARS-CoV-2 infection. Recently, a number of relevant human miRNAs with direct implications in COVID-19 have been identified.
Relevance of miR-16 to COVID-19
SARS-CoV-2 appears to reduce the levels of miR-16 in infected cells to facilitate viral replication and survival. Given that miR-16 plays an important role in inducing apoptosis by reducing the levels of a protein that promotes cell survival, viral sequestration of this miRNA prevents cell death. Normally, the body tries to induce apoptosis in virally infected cells to prevent subsequent viral replication and to facilitate elimination of the virus by macrophages. By downregulating miR-16, SARS-CoV-2 may evade this immune mechanism by stopping apoptosis, allowing the cell to survive for longer to act as a viral factory.
Moreover, the suppression of miR-16 has also been shown to increase TLR4 expression and promote free radical production. This is highly relevant given that that TLR4 expression and free radicals can induce lung damage, which is a clinical feature of COVID-19. When SARS-CoV-2 infects lung cells, it leads to increased free radical production and macrophage infiltration, which may in turn result in lung scarring. These observations suggest that the suppression of miR-16 by SARS-CoV-2 may not only enhance viral replication, but it could also induce lung damage through an amplification of inflammatory pathways. Consequently, the upregulation of miR-16 through the development of miRNA mimics may be an interesting option to simultaneously combat COVID-19 infection and reduce lung-related complications.
Relevance of miR-200b/c to COVID-19
Other miRNAs that may be particularly relevant for SARS-CoV-2 infection are miR-200b and miR-200c. These miRNAs appear to be involved in regulating the expression of a protein known as ACE2, which is an important regulator of heart and lung function. Unfortunately, this important protein is also relevant to COVID-19 because it is used by SARS-CoV-2 to attach and penetrate into host cells. Given that SARS-CoV-2 only infects cells with ACE2, this causes a reduction in the levels of this protein, which may amplify heart and lung damage during COVID-19 infection.
Downregulation of ACE2 expression during COVID-19 infection appears to be caused not only by the direct binding of SARS-CoV-2 to ACE2, but also as a consequence of upregulation of miR-200b/c expression by the virus. To counteract this, developing miR-200b/c inhibitors that upregulate ACE2 expression could be an interesting therapeutic strategy to reduce the risk of developing severe heart and lung complications during SARS-CoV-2 infection.
miRNAs represent an important avenue for understanding how viruses such as SARS-CoV-2 induce changes at a genetic level to suppress or increase the levels of specific proteins that may facilitate viral replication and induce organ damage. Armed with this knowledge, therapeutic approaches that suppress or mimic specific miRNAs represent a novel opportunity to counteract viral replication and to minimise the organ damage incurred during severe COVID-19 infection.
- Hum C, et al. Drugs. 2021;81:517–531.