Most SARS-CoV-2 NAbs recognize epitopes within the ACE2 binding site, imposing direct competition between the virus-ACE2 interaction ( Brouwer et al., 2020 Cao et al., 2020 Hansen et al., 2020 Shi et al., 2020, 2020 Wu et al., 2020), whereas others bind outside the RBM ( Hansen et al., 2020 Pinto et al., 2020 Wang et al., 2020) or even the RBD ( Brouwer et al., 2020 Chi et al., 2020). Since the first report of COVID-19, many SARS-CoV-2 neutralizing monoclonal antibodies (NAbs) have been discovered in immunized animals ( Hansen et al., 2020 Wang et al., 2020 Wrapp et al., 2020a) and COVID-19 convalescent individuals ( Brouwer et al., 2020 Cao et al., 2020 Chi et al., 2020 Hansen et al., 2020 Ju et al., 2020 Lou et al., 2020 Rogers et al., 2020 Shi et al., 2020 Wan et al., 2020 Wu et al., 2020). Preliminary reports also implicate syncytia in chronic cardiovascular injury because of COVID-19 ( Schneider et al., 2020).Ī common therapeutic strategy against COVID-19 and other CoV-related illnesses is blocking the RBD/ACE2 interaction with antibodies, nanobodies, or soluble ACE2 as a decoy ( Zhou and Zhao, 2020). Syncytia are associated with lung tissue damage in SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infection and have been observed widely in autopsies of individuals afflicted with severe coronavirus disease 2019 (COVID-19) ( Bussani et al., 2020 Xu et al., 2020). In addition to mediating virus entry, excess Spike protein in the membranes of CoV-infected cells drives neighboring cells expressing ACE2 to fuse and form syncytia (multinucleated giant cells) through a pH-independent mechanism ( Musarrat et al., 2020 Shulla et al., 2011).
#X morph defense collect debris Patch#
The RBD binds to ACE2 via the receptor binding motif (RBM), a small patch made up of about 20 amino acids ( Lan et al., 2020 Tai et al., 2020).
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SARS-CoV-2 and SARS-CoV use angiotensin-converting enzyme 2 (ACE2) as the entry receptor to infect host cells ( Hoffmann et al., 2020 Walls et al., 2020 Zhou et al., 2020). Further shedding of the S1 subunit exposes the S2 subunit fusion peptide, which inserts into the host cell membrane and induces viral fusion ( Benton et al., 2020).
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Upon binding to the host cell receptor through the receptor binding domain (RBD) at the tip of the S1 subunit, the Spike protein undergoes dramatic conformational changes and proteolytic processing. The SARS-CoV-2 Spike protein, similar to that of other CoVs, comprises two subunits, S1 and S2, and is responsible for target recognition and mediating virus entry ( Tortorici and Veesler, 2019). The virus enters cells by fusion of the viral envelope with cellular plasma membranes and, alternatively, by endocytosis and subsequent fusion of the viral envelope with endosomal membranes. The first step of infection with coronaviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is binding of a Spike protein on the virion to a specific receptor in the membrane of a host cell ( Tortorici and Veesler, 2019). We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19.
#X morph defense collect debris series#
We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes.