Letter to Editor

Elucidation of the underlying mechanism of SARS-CoV-2-mediated cytokine storm syndrome towards enhancing COVID-19 therapeutic modalities

Olanrewaju Ayodeji Durojaye^{1  2  3  *} 
http://orcid.org/0000-0001-8988-8154

¹School of Life Sciences, Department of Molecular and Cell Biology, University of Science and Technology of China, Hefei, China.

² Department of Chemical Sciences, Coal City University, Emene, Enugu State, Nigeria.

³ Department of Biochemistry, University of Nigeria, Nsukka, Enugu State, Nigeria.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has demonstrated a similar infection pattern (with a faster rate of transmission) and clinical features compared to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). However, it is of utmost interest that acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS) and acute lung injury (ALI) occurred in both MERS-CoV- and SARS-CoV-infected individuals, as well as Coronavirus Disease-19 (COVID-19) patients.¹ Specific cytokines have been observed at the core of inflammation development and have also been found to play critical roles in facilitating the exhibition of the aforementioned clinical features. According to reports from previous studies, cytokines such as Tumor Necrosis Factor-α (TNF-α), Macrophage Inflammatory Protein-1A (MIP-1A), monocyte chemoattractant protein-1 (MCP-1), IFN-γ-Inducible Protein 10 (IP10), Granulocyte colony-stimulating factor (GSCF), Interleukin-2 (IL-2), Interleukin-7 (IL-7), Interleukin-10 (IL-10) and Interleukin-17 (IL-17) are significantly increased in COVID-19 patients, with the attributes of a cytokine storm.² Upon infection by SARS-CoV-2, the inflammatory response plays an antiviral function, but an intense cytokine storm as a result of imbalanced response, could have a harmful effect on patients.¹ Therefore, employing approaches that suppresse effectively cytokine storm is required for saving the COVID-19 patients’ lives and to prevent disease deterioration, which is of great significance to reduce mortality rate and for treating patients with severe infection. Elucidation of the mechanism of the SARS-CoV-2-induced cytokine storm may shed more light on the potential therapeutic interventions towards the quelling and prevention of this hazardous process.

Currently, SARS-CoV-2 studies have clarified the basic mechanisms by which the virus invades the host system, but virus replication, its release, and host immune regulation still remains elusive.³ Lin et al.⁴ in a recent study identified that the SARS-CoV-2 Open Reading Frame 8 (ORF8) emulated the IL-17 function through the interaction with the host Interleukin-17 Receptor A (IL17RA), and facilitated the secretion of pro-inflammatory factors through NF-κB signaling pathway activation. The IL-17 pathway is a crucial mammalian pro-inflammatory signaling pathway. Binding of the IL-17 causes activation of the corresponding receptor, leading to the recruitment of ACT1 (NF-κB Activator 1) from the cytoplasm, through the expression of fibroblast growth factor genes and IL-17R (SEFIR) domain. ACT1 signals the TNF receptor-associated factor 6 (TRAF6) to activate the NF-κB signaling pathway, thereby improving the level of expression of pro-inflammatory factors.⁵

Analysis of the clinical data as published by Vaninov,⁶ showed that patients with severe COVID-19 displayed a cytokine storm, leading to multiple organ failure and ARDS.⁶ Cytokine storm is simply the fast production of multiple cytokines, such as the Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-12 (IL-12), Interferon-α (IFN-α) and TNF-α. ARDS caused by cytokine storm in the late stage of SARS-CoV-2 infection is a critical factor in the transition from mild to severe illness and also a crucial cause of death.⁶ In the current COVID-19 treatment, antibodies targeting the IL-6 are mostly used to inhibit the cytokine storm. However, the IL-6 suppression hasn’t achieved any desired effect in clinical treatment.⁷ As a proinflammatory cytokine, IL-17 has been reported to be associated with cytokine storm, making it an immunologically plausible target for ARDS prevention in COVID-19. In addition to the demonstration of the IL-17 function emulation by the ORF8 of SARS-CoV-2, Lin et al.⁴ also found that, inhibition of the interaction between the SARS-CoV-2 ORF8 and the IL17RA by an IL17RA antibody was essential for the control of the cytokine storm in SARS-CoV-2 infection.

In conclusion, COVID-19 since its inception has brought severe challenges to global health, with millions of infected people worldwide and few approved vaccines with a protective effect against viral infection. However, except for a certain understanding of the viral transmembrane spike glycoprotein, the function of other viral proteins is yet to be extensively studied. Uncovering viral pathogenesis from the host-virus interaction perspective such as the interaction between the SARS-CoV-2 ORF8 and the IL17RA, is a necessary approach to advance clinical therapy. Furthermore, considering the hyperactive inflammatory effects of the SARS-CoV-2, agents that modulate the immune response may be explored as therapeutic alternatives for the management of moderate to critical COVID-19.

References/Referencias

1. Song P, Li W, Xie J, Hou Y, You C. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta. 2020; 509:280-7. doi: https://10.1016/j.cca.2020.06.017.

2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi: https://10.1016/S0140-6736(20)30183-5. Erratum in: Lancet. 2020; 395(10223):496. doi: https://10.1016/S0140-6736(20)30252-X.

3. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-80.e8. doi: https:// 10.1016/j.cell.2020.02.052.

4. Lin X, Fu B, Yin S, Li Z, Liu H, Zhang H, et al. ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway. iScience. 2021;24(4):102293. doi: https://10.1016/j.isci.2021.102293.

5. McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 Family of Cytokines in Health and Disease. Immunity. 2019;50(4):892-906. doi: https://10.1016/j.immuni.2019.03.021.

6. Vaninov N. In the eye of the COVID-19 cytokine storm. Nat Rev Immunol. 2020;20(5):277. doi: https://10.1038/s41577-020-0305-6.

7. Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, Ravaud P, CORIMUNO-19 Collaborative Group. Effect of Tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: A randomized clinical trial. JAMA Intern Med. 2021;181(1):32-40. doi: https://10.1001/jamainternmed.2020.6820. Erratum in: JAMA Intern Med. 2021;181(1):144. Erratum in: JAMA Intern Med. 2021;181(7):1021.

Received: August 10, 2021; Accepted: September 16, 2021

Corresponding author: [e-mail]

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BSc Biochemistry Olabisi Onabanjo University, Ago-Iwoye, Nigeria. MSc Molecular Biology, University of Nigeria, Nsukka, Nigeria. Molecular and Cell Biology doctoral scholar, University of Science and Technology of China. Biochemistry lecturer, Coal City Univeristy, Emene, Enugu State, Nigeria.