A combinational approach to restore cytokine balance and to inhibit virus growth may promote patient recovery in severe COVID-19 cases

Abstract

The COVID-19 pandemic has led to twin public health and economic crises around the world. Not only has it cost hundreds of thousands of lives but also severely impacted livelihoods and placed enormous strain on community healthcare and welfare services. In this review, we explore the events associated with SARS-CoV-2 pathogenesis and host immunopathological reactivity due to the clinical manifestations of this coronavirus infection. We discuss that the metallopeptidase enzyme ADAM17, also known as tumor necrosis factor-α-converting enzyme, TACE, is responsible for shedding of angiotensin-converting enzyme 2 and membrane-bound interleukin (IL)-6 receptor. This leads to elevated pro-inflammatory responses that result in cytokine storm syndrome. We argue that cytokine balance may be restored by recovering an IL-6 trans-signaling neutralizing buffer system through the mediation of recombinant soluble glycoprotein 130 and recombinant ADAM17/TACE prodomain inhibitor. This cytokine restoration, possibly combined with inhibition of SARS-CoV-2 entry as well as replication and coagulopathy, could be introduced as a novel approach to treat patients with severe COVID-19. In cases of co-morbidity, therapies related to the management of associated disease conditions could ameliorate those clinical manifestations.

Keywords: ADAM17; ADAM17/TACE inhibitor; COVID-19; IL-6; SARS-CoV-2; TACE; Therapy; sgp130Fc.

Fig. 1

Establishment of cytokine storm in COVID-19. From upper left to right: SARS-CoV-2 binds with ACE2, thereby facilitating entry of viral RNA into the host cell; ACE2 is shed by ADAM17; Ang II triggers pro-inflammatory responses via M1 macrophages. Centre: IL-6/sIL-6R complexes are neutralized by sgp130 until the concentration of sIL-6R is lower than that of IL-6. Lower left: When infection is activated ADAM17 triggers IL-6R shedding. Once the concentration of sIL-6R is higher than that of IL-6, sgp130 cannot neutralize increased levels of IL-6/sIL-6R complexes. IL-6 trans-signaling is triggered and, as a consequence, cytokine storm is initiated.

Fig. 2

Proposed therapeutic model. Administration of sgp130Fc suppresses IL-6 trans-signaling by trapping available IL-6/sIL-6R complexes (upper section). TPD inhibits ADAM17 activation and stops shedding of ACE2 and IL-6 receptors. As a consequence, the concentration of sIL-6R becomes lower than that of IL-6, whereupon IL-6 switches from trans- to classical-signaling. By this means, regulation of cytokine storm may be achieved, while antiviral therapy will restrict viral host cell entry.