Role of ACE2 and TMPRSS2 in SARS-CoV-2 cell entry and investigation of an antiviral strategy

The recent outbreak of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, has posed a serious threat to public health. The virus spread globally and became a pandemic declared by the World Health Organization (WHO), in March 2020. To develop an effective therapeutic approach, it is mandatory to gain more insight on the molecular mechanisms exploited by SARS-CoV-2 to infect human cells. In particular, a fundamental step of the infection process, herein investigated, is the viral host cell entry. The first analysed article of Hoffmann et al., published on "Cell" (2020), demonstrated that SARS-CoV-2 utilizes its transmembrane spike (S) protein to mediate the virion attachment on cellular membrane through the recognition of Angiotensin converting enzyme 2 (ACE2), which is proved to be the critical receptor for viral entry. However, ACE2 is not sufficient for SARS-CoV-2 infection, indeed the serine protease TMPRSS2 is necessary for the S protein priming by means of the S1/S2 and S2’ cleavage that promotes the fusion between viral and cellular membranes. Furthermore, investigation of a possible antiviral strategy is performed utilizing the TMPRSS2 inhibitor camostat mesylate, which is proven to actively block, but not abrogate, SARS-CoV-2 cell entry, due to the presence of the endosomal cysteine proteases cathepsin B/L. The second analysed work of Wang et al., published on "Cell" (2020), confirmed that SARS-CoV-2 exploits its S protein for host cell entry and revealed that the virus specifically applies its C-terminal domain (CTD), included in the S protein, to interact with the human receptor ACE2. Besides, the reported crystal structure of SARS-CoV-2-CTD in complex with ACE2 showed increased atomic interactions, especially at the level of the β1’/β2’ loop, and exhibited 4-fold stronger affinity compared to SARS-CoV-RBD bound to ACE2. Indeed, the binding between the virus and ACE2 appeared to be specific, which could explain the high transmissibility of SARS-CoV-2. In the third analysed paper of Sungnak et al., published on "Nature Medicine" (2020), viral entry-associated genes are investigated by means of single-cell RNA-sequencing data from multiple tissues from healthy human donors. Both ACE2 and TMPRSS2 are reported to be co-expressed mainly in goblet/secretory and ciliated nasal epithelial cells, suggesting that the upper airway is the major infection site of SARS-CoV-2, consistent with COVID-19 symptoms. Moreover, ACE2-correlated genes are identified to be genes associated with immune functions, highlighting the cells’ potential role in initial viral infection, spread and clearance. Overall these findings shed light on SARS-CoV-2 entry and pathogenesis and provide important structural information hopefully inspiring novel potential therapeutic countermeasures against the emerging virus.