Advances in research on ACE2 as a receptor for 2019-nCoV

Abstract

Currently, a novel coronavirus (SARS-CoV-2, also called 2019-nCoV) has triggered pandemic Coronavirus Disease 2019 (COVID-19), an acute infectious respiratory disease that first became epidemic in Wuhan (China) and is now spreading worldwide. Although 2019-nCoV and SARS-CoV are very similar viruses genomically and structurally, the huge number of severe cases and deaths now being caused by 2019-nCoV infections has understandably prompted intense research on the receptor used by it to enter human cells. Angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. In this review, we describe the roles performed by ACE2 as an enzymatic catalyst and as a receptor for this novel coronavirus. We also summarize the latest research pertaining to the changes noted in ACE2 expression after viral binding, and the relationships relating to virus transmission and population susceptibility to it. Lastly, we speculate on the pathogenesis of COVID-19 and provide a useful reference for drug development against this aggressive virus.

Keywords: 2019-nCoV; Angiotensin converting enzyme 2; Coronavirus; Immune function; Renin angiotensin system; Virus receptor.

Fig. 1

The metabolic pathway of the rennin–angiotensin system. The RAS system mainly encompasses two axes: the classical RAS ACE–Ang II–AT1 regulatory axis and the ACE2–Ang–(1–7)–Mas counter-regulatory axis. (P) RR, (pro) renin receptor; Ang, angiotensin; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; NEP, neutral endopeptidase; PEP, prolyl endopeptidase; PCP, prolyl carboxypeptidase

Fig. 2

The viral invasion process of host cells via the ACE2 receptor. ACE2 as a receptor may mediate the entry of CoV into host cells via two distinct routes. The first involves clathrin-dependent endocytosis; the second involves ACE2 receptor-mediated TMPRSS2-dependent membrane fusion. ADAM17, a disintegrin and metallopeptidase domain 17; TMPRSS2, transmembrane serine protease 2

Fig. 3

The proposed mechanism underlying 2019-nCoV-induced downregulation of cell surface ACE2 expression. CoV interacting with ACE2 becomes internalized together with ACE2 through endocytosis, which upregulates ADAM17-mediated proteolytic cleavage of ACE2. Loss of ACE2 leads to accumulation of angiotensin II, which also increases ADAM17 activity through AT1 receptors. rhACE2 inhibits viral invasion of host cells by competitive binding to CoV with membrane ACE2, limits the activities of Ang II, and increases protective Ang-(1–7) levels

Fig. 4

Changes of ACE2 expression and key role of immune function after 2019-CoV infection. Invasion of 2019-nCoV to host cells induces nonspecific reactions of local tissue, releasing cytokines such as TNF-α, IFNs, and so on. The expression of ACE2 may be downregulated by endocytosis and TNF-α. At this point, although the viral invasion decreases, the local RAS is imbalance, reducing its anti-inflammatory effect. The expression of ACE2 may be upregulated by IFNs, enhancing the anti-inflammatory effect of local RAS, but also providing more entry for virus. Therefore, when cells and viruses fight, the human cellular and humoral immune function is particularly important. The insufficient or excessive immune responses will destroy their own tissue cells as a result of virus replication or cytokine storm. Only moderate immunity can clear viruses and restore cells