Potential Detrimental Role of Soluble ACE2 in Severe COVID-19 Comorbid Patients

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) takes its entry to host cell via angiotensin converting enzyme 2 (ACE2) receptor. Biochemical and structural analysis indicate the roles of other important proteins and/or enzymes involved in this process including disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) also known as tumor necrosis factor-α-converting enzyme (TACE) and trans membrane serine protease 2 (TMPRSS2). As a biological protective mechanism ACE2 converts angiotensin II (Ang II) to angiotensin (1-7) and helps to balance renin angiotensin system (RAS). Being the key receptor for virus spike binding and subsequent role in viral entry, the detrimental effect of ACE2 is also of great concern. Membrane-bound ACE2 ectodomain is shedded by ADAM17 upon viral spike binding, Ang II overproduction and in some disease condition. The shedded soluble ACE2 (sACE2) retains its catalytic activity, but its exact role in viral entry and pathogenesis is still unclear. It has been claimed that therapeutic sACE2 which mimic the ectodomain can exert dual effects; reduction of excess Ang II and blocking the viral entry by masking spike protein. But the important concern is why SARS-CoV-2 comorbid patients having higher amount of sACE2 cannot attain such benefit in viral infection. At this context, in this perspective we partially argue about the protective role of sACE2 and hypothesize that sACE2 can convert Ang II but we additionally speculate a series of events where protease primed or non-primed virus-sACE2 complex can possibly take entry inside the host cell. As floating virus can bind a good number of sACE2, upon endocytosis by host cell, extracellular sACE2 level could be reduced drastically. As a consequence, rapid rise in Ang II level can potentially aggravate disease severity through Ang II-angiotensin receptor 1 (AT1R) axis in comorbid patients. Thus, therapeutic recombinant sACE2 should be designed accordingly to achieve maximum outcome in treating COVID-19.