Searching in the deep sea of data for clues

Recently, the KnetMiner team released the COVID-19 Human KnetMiner, as detailed in their press release and in Nature. Countless hours of hard work and effort were put into its creation. Wanting to get it out to the public domain as soon as possible, no specific use-cases were given. But, using the KnetMiner, it’s very apparent that there are highly relevant and important discoveries to be made with it. One specific use case is that related to corticosteroids and coronvavirus.

Why specifically corticosteroids? The reason for this is due to the initial widespread use of corticosteroids for patients with COVID-19 (Zha et al., 2020) and also because inhaled corticosteroids can increase the risk of pneuomnia in asthmatic patients (Kim et al., 2018). Literature is clear that SARS-CoV-2 can trigger asthma exacerbations and increase the risk of pneumonia (Abrams, Geert W. and Yang, 2020; Ren et al., 2020).

Therefore, we searched for “coronavirus AND corticosteroids” using the COVID-19 Human KnetMiner. This returned IL6, IL1B, CRP, and TMPRSS2. Of course, CRP and cytokine genes are to be expected due to corticosteroids well-characterised anti-inflammatory and immunosupressive actions, thus acting upon cytokines and reducing inflammatory markers like CRP. Of particular interested was TMPRSS2, given the clear role we now understand it to play in coronavirus. TMPRSS2 helps facilitate cell entry of SARS-CoV-2 (Hoffmann et al., 2020).

Figure 1 – knowledge network for TMPRSS2 with info panel for drug (cicleosnide)-publication (Mastuyama et al., 2020) relationship.

This particular network made several references to both proteins ACE2 and TMPRSS2 in their positive regulation of viral entry to the hosts cells. Of notable interest was a paper (Mastuyama et al., 2020) that was identified to be associated with TMPRSS2 and its drug relationships with Ciclesonide and Mifepristone. The relationships detailed that in vitro, both drugs were effectively able to block SARS-CoV-2 replication, presuming that in Ciclesonide this was due to an inhibitory interaction with SARS-CoV-2 viral NSP15. Additionally, the paper suggested that both drugs have a decreased immunosupressive effect versus other systemic corticosteroids, owed to its high lung tissue selectivity. Likewise, clinical safety has been established. This suggests that Ciclesonide and potentially Mifepristone are potential drug candidates for follow up clinical trials, particular to treat asthmatic patients, without detrimental effects that could see to a worsening condition when infected with SARS-CoV-2.

Finding this paper is demonstrative of the power that KnetMiner beholds. A deep dive into the vast sea of data to find treasures requires the right tools; KnetMiner proved itself to be effective at demonstrating the most well linked genes here. Likewise, it identified highly relevant papers that can be of great use in our ongoing battle against the COVID-19 2020 pandemic.

This is just one of a few use-cases already identified. To help find more, please use our COVID-19 KnetMiner!

References

1. Abrams, E., Geert W., ‘. and Yang, C., 2020. Asthma and COVID-19. Canadian Medical Association Journal, p.cmaj.200617.
2. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T., Herrler, G., Wu, N., Nitsche, A., Müller, M., Drosten, C. and Pöhlmann, S., 2020. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181(2), pp.271-280.e8.
3. Kim, M., Rhee, C., Shim, J., Park, S., Yoo, K., Kim, B., Bae, H., Sim, Y., Chang, J., Cho, Y. and Lee, J., 2019. Inhaled Corticosteroids in Asthma and the Risk of Pneumonia. Allergy, Asthma & Immunology Research, 11(6), p.795.
4. Matsuyama, S., Kawase, M., Nao, N., Shirato, K., Ujike, M., Kamitani, W., Shimojima, M. and Fukushi, S., 2020. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15.
5. Ren, L., Wang, Y., Wu, Z., Xiang, Z., Guo, L., Xu, T., Jiang, Y., Xiong, Y., Li, Y., Li, X., Li, H., Fan, G., Gu, X., Xiao, Y., Gao, H., Xu, J., Yang, F., Wang, X., Wu, C., Chen, L., Liu, Y., Liu, B., Yang, J., Wang, X., Dong, J., Li, L., Huang, C., Zhao, J., Hu, Y., Cheng, Z., Liu, L., Qian, Z., Qin, C., Jin, Q., Cao, B. and Wang, J., 2020. Identification of a novel coronavirus causing severe pneumonia in human. Chinese Medical Journal, 133(9), pp.1015-1024.
6. Zha, L., Li, S., Pan, L., Tefsen, B., Li, Y., French, N., Chen, L., Yang, G. and Villanueva, E., 2020. Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Medical Journal of Australia,.