TMPRSS2 reduces antibody recognition of SARS-CoV-2 spike

Abstract The serine protease TMPRSS2 acts as a cofactor for SARS-CoV-2 entry by cleaving the viral spike (S) to initiate fusion. Whether TMPRSS2 has an impact on humoral immune response against S remains poorly characterized. Here, we show that TMPRSS2 impairs antibody binding to S. In S-expressing and infected cells, TMPRSS2 decreases monoclonal antibody (mAb) and immune serum binding, as well as antibody-dependent cellular cytotoxicity (ADCC) induction. Using a panel of 39 mAbs targeting various S regions, we observe that those binding to the S2 subunit are the most affected by TMPRSS2. TMPRSS2 promotes a partial shedding of S1 and changes S2 conformation. This processing reduces Angiotensin-Converting Enzyme 2 (ACE2) binding while increasing cell-cell fusion. We further observe that the capacity of TMPRSS2 to decrease antibody recognition is conserved across coronaviruses and shared with other TMPRSS proteins. However, TMPRSS2 expression in infected cells does not impact significantly virions’ infectivity or the antibody recognition, as measured by flow virometry. Collectively, our findings suggest that TMPRSS2 processing of S favors a fusion intermediate conformation which is less sensitive to antibody recognition.