Infectivity of pseudotyped SARS‐CoV‐2 variants of concern in different human cell types and inhibitory effects of recombinant spike protein and entry‐related cellular factors

Abstract Since the report of the first COVID‐19 case in 2019, SARS‐CoV‐2 variants of concern (VOCs) have continued to emerge, manifesting diverse infectivity, evasion of host immunity and pathology. While ACE2 is the predominant receptor of SARS‐CoV‐2, TMPRSS2, Kim‐1, NRP‐1, CD147, furin, CD209L, and CD26 have also been implicated as viral entry‐related cofactors. To understand the variations in infectivity and pathogenesis of VOCs, we conducted infection analysis in human cells from different organ systems using pseudoviruses of VOCs including Alpha, Beta, Gamma, and Delta. Recombinant spike S1, RBD, ACE2, Kim‐1, and NRP‐1 proteins were tested for their ability to block infection to dissect their roles in SARS‐CoV‐2 entry into cells. Compared with wild type SARS‐CoV‐2 (WT), numerous VOCs had significant increases of infectivity across a wide spectrum of cell types. Recombinant ACE2 protein more effectively inhibited the infection of VOCs including Delta and Omicron (BA.1 and BA.2) than that of WT. Interestingly, recombinant S1, RBD, Kim‐1, and NRP‐1 proteins inhibited the infection of all pseudoviruses in a manner dependent on the levels of ACE2 expression in different cell types. These results provide insights into the diverse infectivity of SARS‐CoV‐2 VOCs, which might be helpful for managing the emergence of new VOCs.