miRNA: interaction between the host and the virus

By Ashley Lai

The interaction between host cell miRNAs and the virus is vital for virus pathogenesis. MicroRNAs (miRNAs) are short non-coding RNAs that regulate the protein expression by mRNA cleavage, degradation and hence repressing their translation (Wahid et al., 2010). Therefore during infections, cellular miRNAs are also involved in regulating their immune response and signalling. Hepatitis C virus (HCV) RNA induces transcription of NF‐κB which in turn upregulate miR-155 (Zhang et al., 2012). The signalling pathway in memory T cell, Th17 differentiation is promoted by miR-155, where it can suppress proteins that negatively regulate this signalling pathway (O’Connell et al., 2010). miR-155 can also target SOCS1 to activate the JAK/STAT signalling, inducing an innate antiviral immune response and autoimmune inflammatory (Jiang et al., 2014).

Although host cell can use their own miRNAs to suppress the infection, some viruses developed mechanisms that can hijack the host miRNA for their own benefit regarding reproducibility and pathogenesis. For example, to create a favourable environment for replication and avoid the immune response. The oncogenic herpesvirus, Herpesvirus saimiri, can use its seven small nuclear RNA (HSUR1-7) to alter the level of the host miRNA, miR-27. The region on HSUR1 has to be conformationally flexible and complementary to the 3’ end of the miR-27 for efficient degradation. Downregulation of miR-27 means other oncogenic proteins are not silenced by miR-27, contributing to oncogenesis by escaping the immune system. (Paulina, Moss and Steitz, 2016)

Some DNA viruses replicated in the nucleus synthesize their own viral miRNAs using host RNA machinery. Viral miRNA has a great advantage over viral proteins as they are less likely to be recognised by the host cell, useful in regulating the infection latency. They can be classified into 2 groups and about 26% of viral miRNAs have similar sequence as the target sites on host miRNAs. During evasion, it can post-transcriptionally regulate both host and viral genes, for example, inhibit the transcription of genes for apoptosis and antiviral-responses (Kincaid and Sullivan, 2012). H5N1 Influenza virus can synthesis miR-HA-3p via the host cell’s Dicer and Drosha-independent pathway. The sequence is highly conserved within 455 strains, demonstrating how functionally important it is. miR-HA-3p can bind and inhibit poly(rC)-binding protein 2 (PCBP2), a hnRNP, using a specific motif of single-stranded polyC nucleotides. PCBP2 negatively regulate the MAVS-mediated antiviral signalling pathway. Binding of PCBP2 to MAVS will lead to degradation of MAVS, suppressing the inflammatory response by the host cell. Excessive production of cytokines was also promoted by the silencing of PCBP2(Li et al., 2018). The other group is viral-specific, which many of their mechanisms and functions still remains unclear(Kincaid and Sullivan, 2012). HHV-6A miR-U86 is an example of viral-specific miRNA that doesn’t share any homology with host miRNAs. It was found that HHV-6A miR-U86 plays a role in inhibiting the protein expression level of HHV-6A IE2 transcript and regulating latency and the viral lytic replication. (Nukui, Mori and Murphy, 2015) The precise mechanism of viral-specific miRNA still requires research and could potentially be a target for future treatments.

Interestingly during SARS-CoV-2 infection, both cellular and viral miRNA were used by the virus to facilitate entry and inhibit the host’s immune response. Induced cellular miRNA interferes with a wide range of intracellular signalling pathways, for example, the CXCR4 and mTOR signalling pathway to avoid apoptosis during the early stage of infection. They can reduce the downstream signalling of Toll-like receptors, which is one of the important stimulatory molecule required to produce interferons and cytokines. Besides, some viral miRNA was shown to target and deregulate genes involved in both the host insulin-signalling and heart development-related pathways. This might explain the correlation between symptom severity and infected patient with an existing health condition, such as diabetes and cardiovascular issues. (Khan et al., 2020)

Potential miRNA-based treatments regarding SARS-CoV-2 are rapidly developing. Researchers have predicted that seven complete complementary miRNA (cc-miRNA) can suppress translation of viral protein via binding to ORF1ab, S and N ssRNA in SARS-CoV-2. As cc-miRNA only shows weak binding to human mRNA, translation of human cellular proteins are suggested to be not affected and any risk of possible side effects are lower. The overall cc-miRNA concentration required is relatively lower and a combination of different cc-miRNA can be applied in drugs for SARS-CoV-2 infected patients. (Rakhmetullina et al., 2021)

Many target proteins in SARS-CoV-2 have been identified, for example, the transmembrane serine protease, Tmprss2, that is required to cleave the spike protein into S1 and S2 subunit for the entry of the virus. Three prediction computer tools, miRDB, TargetScanHuman and miRanda have been used to identify three human miRNA, miR214, miR98 and miR32 that can bind specifically and silence the Tmprss2 mRNA. Among the three miRNA, miR32 shows the highest suppression of Tmprss2. Tmprss2 is also involved in several cancers development, such as the tumour cell migration in breast cancer, and hence the development in therapies based on this miRNA will also benefit other diseases (Kaur et al., 2021). In addition, a miRNA target prediction algorithm has been used to identify twenty-four miRNAs that can regulate the expression level of another target, the ACE2 receptor in respiratory host cells. The TargetScan algorithm is also used to predict the binding position of miR-200c-3p and miR-200b-3p with ACE2 receptor. It suggested miRNA-based therapies can be developed against SARS-CoV-2 infections and delivered by liposome-like exosomes and inorganic nanoparticles (Bozgeyik, 2021).

Nonetheless, the global miRNA-virus interactome still remains unclear. Host miRNA could be beneficial to both the host and the pathogenesis of the virus. This dual properties of miRNA should be investigated further, especially using bioinformatics tools and machine learning, for future developments of miRNA-based or RNAi-based therapies against the virus. 

References:

Bozgeyik, I. (2021) Therapeutic potential of miRNAs targeting SARS-CoV-2 host cell receptor ACE2. Meta Gene. 27 100831. Available from: https://doi.org/10.1016/j.mgene.2020.100831.

Jiang, M., Broering, R., Trippler, M., Wu, J., Zhang, E., Zhang, X., Gerken, G., Lu, M. & Schlaak, J. F. (2014) MicroRNA-155 controls Toll-like receptor 3- and hepatitis C virus-induced immune responses in the liver. Journal of Viral Hepatitis. 21 (2), 99-110. Available from: https://doi.org/10.1111/jvh.12126. 

Kaur, T., Kapila, S., Kapila, R., Kumar, S., Upadhyay, D., Kaur, M. & Sharma, C. (2021) Tmprss2 specific miRNAs as promising regulators for SARS-CoV-2 entry checkpoint. Virus Research. 294 198275. Available from: https://doi.org/10.1016/j.virusres.2020.198275.

Khan MA-A-K, Sany MRU, Islam MS and Islam ABMMK (2020) Epigenetic Regulator miRNA Pattern Differences Among SARS-CoV, SARS-CoV-2, and SARS-CoV-2 World-Wide Isolates Delineated the Mystery Behind the Epic Pathogenicity and Distinct Clinical Characteristics of Pandemic COVID-19. Front. Genet. 11:765. Available from:10.3389/fgene.2020.00765

Kincaid, R. P. & Sullivan, C. S. (2012) Virus-Encoded microRNAs: An Overview and a Look to the Future. PLOS Pathogens. 8 (12), e1003018. Available from: https://doi.org/10.1371/journal.ppat.1003018.

Li, X., Fu, Z., Liang, H., Wang, Y., Qi, X., Ding, M., Sun, X., Zhou, Z., Huang, Y., Gu, H., Li, L., Chen, X., Li, D., Zhao, Q., Liu, F., Wang, H., Wang, J., Zen, K. & Zhang, C. (2018) H5N1 influenza virus-specific miRNA-like small RNA increases cytokine production and mouse mortality via targeting poly(rC)-binding protein 2. Cell Research. 28 (2), 157-171. Available from: https://doi.org/10.1038/cr.2018.3. 

Nukui, M., Mori, Y. & Murphy, E. A. (2015) A human herpesvirus 6A-encoded microRNA: role in viral lytic replication. Journal of Virology. 89 (5), 2615-2627. Available from: 10.1128/JVI.02007-14.

O’Connell, R. M., Kahn, D., Gibson, W. S. J., Round, J. L., Scholz, R. L., Chaudhuri, A. A., Kahn, M. E., Rao, D. S. & Baltimore, D. (2010) MicroRNA-155 Promotes Autoimmune Inflammation by Enhancing Inflammatory T Cell Development. Immunity. 33 (4), 607-619. Available from: https://doi.org/10.1016/j.immuni.2010.09.009.

Pawlica, P., Moss, W. N. & Steitz, J. A. (2016) Host miRNA degradation by Herpesvirus saimiri small nuclear RNA requires an unstructured interacting region. Rna. 22 (8), 1181-1189. Available from: http://rnajournal.cshlp.org/content/22/8/1181.abstract. 

Rakhmetullina, A., Ivashchenko, A., Akimniyazova, A., Aisina, D. & Pyrkova, A. (2021) The miRNA COMPLEXES AGAINST CORONAVIRUSES SARS-CoV-2, SARS-CoV, and MERS-CoV. Research Square. Available from: https://doi.org/10.21203/rs.3.rs-20476/v2.

Wahid, F., Shehzad, A., Khan, T. & Kim, Y. Y. (2010) MicroRNAs: Synthesis, mechanism, function, and recent clinical trials. Biochimica Et Biophysica Acta (BBA) – Molecular Cell Research. 1803 (11), 1231-1243. Available from: https://doi.org/10.1016/j.bbamcr.2010.06.013.

Zhang, Y., Wei, W., Cheng, N., Wang, K., Li, B., Jiang, X. & Sun, S. (2012) Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology. 56 (5), 1631-1640. Available from: https://doi.org/10.1002/hep.25849.