Abstract: The severe acute syndrome coronavirus 2(SARS-CoV-2)is responsible for the global pandemic of 2019 novel coronavirus disease(COVID-19). Understanding the pathogenic mechanisms of SARS-CoV-2 is of great significance to the prevention and control of the COVID-19 epidemic. The spike(S)protein of SARS-CoV-2 is a major target of protective immunity. The mutations of S protein impact the transmission and pathogenic capacity of SARS-CoV-2. In addition, angiotensin-converting enzyme 2(ACE2)is the receptor of SARS-CoV-2 S protein and mediates viral entry into target cells. The genetic polymorphisms of the ACE2 gene may lead to the difference of incidence of COVID-19 among different populations. Protease can promote the infection of SARS-Cov-2 by activating the S protein. This review summarized the current understanding of the function and genetic variants of S protein, ACE2, and the related proteases. The synergistic effect of these three molecules on the susceptibility of SARS-CoV-2 infection was further discussed.