Potential modes of placental invasion by SARS-CoV-2. (1) Antibody-dependent enhancement (ADE): the antibody neutralizing SARS-CoV-2 binds its Fc region onto FCγR, expressed on the apical pole of the trophoblast. Then the neutralized virus is transcytosed into the basic pole, releasing the virus into the fetal extracellular matrix. (2) ACE2/TMPRSS2 pathway: the S2 subunit of the S protein interacts with ACE2 on the apical pole, promoting the fusion of the envelope with the membrane. This is followed by a proteolytic cleavage between S1 and S2 subunits by TMPRSS2, thus releasing the virus. The positive RNA translates the viral-RNA-dependent RNA polymerase and the viral proteins. Then this polymerase produces a high copy number of the viral genome, after which the virion is assembled and released on the basal pole. (3) Cell-to-cell contact: LFA1 expressed on infected T cells interacts with ICAM1 expressed on the trophoblast apical pole, forming a tight interaction and close proximity between two membranes. Thus, the viral release in the placental immune synapse can facilitate viral infection. (4) CD147 expressed on the apical pole of the trophoblast interacts with viral particles, promoting viral infection. Created with BioRender.com.