PMC:7102599 / 1798-9727 JSON TXT

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LitCovid-PubTator

LitCovid-PD-FMA-UBERON

LitCovid_AGAC

{"project":"LitCovid_AGAC","denotations":[{"id":"p52222s6","span":{"begin":3887,"end":3895},"obj":"PosReg"},{"id":"p52222s8","span":{"begin":3900,"end":3907},"obj":"Protein"},{"id":"p52243s16","span":{"begin":6252,"end":6261},"obj":"PosReg"},{"id":"p52243s17","span":{"begin":6262,"end":6303},"obj":"MPA"}],"text":"Introduction\nThree coronaviruses have crossed the species barrier to cause deadly pneumonia in humans since the beginning of the 21st century: severe acute respiratory syndrome coronavirus (SARS-CoV) (Drosten et al., 2003, Ksiazek et al., 2003), Middle-East respiratory syndrome coronavirus (Zaki et al., 2012) (MERS-CoV), and SARS-CoV-2 (Huang et al., 2020, Zhu et al., 2020). SARS-CoV emerged in the Guangdong province of China in 2002 and spread to five continents through air travel routes, infecting 8,098 people and causing 774 deaths. In 2012, MERS-CoV emerged in the Arabian Peninsula, where it remains a major public health concern, and was exported to 27 countries, infecting a total of ∼2,494 individuals and claiming 858 lives. A previously unknown coronavirus, named SARS-CoV-2, was discovered in December 2019 in Wuhan, Hubei province of China and was sequenced and isolated by January 2020 (Zhou et al., 2020, Zhu et al., 2020). SARS-CoV-2 is associated with an ongoing outbreak of atypical pneumonia (Covid-2019) that has affected over 90,000 people and killed more than 3,000 of those affected in \u003e60 countries as of March 3, 2020. On January 30, 2020, the World Health Organization declared the SARS-CoV-2 epidemic a public health emergency of international concern.\nMERS-CoV was suggested to originate from bats, but the reservoir host fueling spillover to humans is unequivocally dromedary camels (Haagmans et al., 2014, Memish et al., 2013). Both SARS-CoV and SARS-CoV-2 are closely related and originated in bats, who most likely serve as reservoir host for these two viruses (Ge et al., 2013, Hu et al., 2017, Li et al., 2005b, Yang et al., 2015a, Zhou et al., 2020). Whereas palm civets and racoon dogs have been recognized as intermediate hosts for zoonotic transmission of SARS-CoV between bats and humans (Guan et al., 2003, Kan et al., 2005, Wang et al., 2005), the SARS-CoV-2 intermediate host remains unknown. The recurrent spillovers of coronaviruses in humans along with detection of numerous coronaviruses in bats, including many SARS-related coronaviruses (SARSr-CoVs), suggest that future zoonotic transmission events may continue (Anthony et al., 2017, Ge et al., 2013, Hu et al., 2017, Li et al., 2005b, Menachery et al., 2015, Menachery et al., 2016, Yang et al., 2015a, Zhou et al., 2020). In addition to the highly pathogenic zoonotic pathogens SARS-CoV, MERS-CoV, and SARS-CoV-2, all belonging to the β-coronavirus genus, four low-pathogenicity coronaviruses are endemic in humans: HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E. To date, no therapeutics or vaccines are approved against any human-infecting coronaviruses.\nCoronavirus entry into host cells is mediated by the transmembrane spike (S) glycoprotein that forms homotrimers protruding from the viral surface (Tortorici and Veesler, 2019). S comprises two functional subunits responsible for binding to the host cell receptor (S1 subunit) and fusion of the viral and cellular membranes (S2 subunit). For many CoVs, S is cleaved at the boundary between the S1 and S2 subunits, which remain non-covalently bound in the prefusion conformation (Belouzard et al., 2009, Bosch et al., 2003, Burkard et al., 2014, Kirchdoerfer et al., 2016, Millet and Whittaker, 2014, Millet and Whittaker, 2015, Park et al., 2016, Walls et al., 2016a). The distal S1 subunit comprises the receptor-binding domain(s) and contributes to stabilization of the prefusion state of the membrane-anchored S2 subunit that contains the fusion machinery (Gui et al., 2017, Kirchdoerfer et al., 2016, Pallesen et al., 2017, Song et al., 2018, Walls et al., 2016a, Walls et al., 2017b, Yuan et al., 2017). For all CoVs, S is further cleaved by host proteases at the so-called S2′ site located immediately upstream of the fusion peptide (Madu et al., 2009, Millet and Whittaker, 2015). This cleavage has been proposed to activate the protein for membrane fusion via extensive irreversible conformational changes (Belouzard et al., 2009, Heald-Sargent and Gallagher, 2012, Millet and Whittaker, 2014, Millet and Whittaker, 2015, Park et al., 2016, Walls et al., 2017b). As a result, coronavirus entry into susceptible cells is a complex process that requires the concerted action of receptor-binding and proteolytic processing of the S protein to promote virus-cell fusion.\nDifferent coronaviruses use distinct domains within the S1 subunit to recognize a variety of attachment and entry receptors, depending on the viral species. Endemic human coronaviruses OC43 and HKU1 attach via their S domain A (SA) to 5-N-acetyl-9-O-acetyl-sialosides found on glycoproteins and glycolipids at the host cell surface to enable entry into susceptible cells (Hulswit et al., 2019, Tortorici et al., 2019, Vlasak et al., 1988). MERS-CoV S, however, uses domain A to recognize non-acetylated sialoside attachment receptors (Li et al., 2017, Park et al., 2019), which likely promote subsequent binding of domain B (SB) to the entry receptor, dipeptidyl-peptidase 4 (Lu et al., 2013, Raj et al., 2013). SARS-CoV and several SARS-related coronaviruses (SARSr-CoV) interact directly with angiotensin-converting enzyme 2 (ACE2) via SB to enter target cells (Ge et al., 2013, Kirchdoerfer et al., 2018, Li et al., 2005a, Li et al., 2003, Song et al., 2018, Yang et al., 2015a).\nAs the coronavirus S glycoprotein is surface-exposed and mediates entry into host cells, it is the main target of neutralizing antibodies (Abs) upon infection and the focus of therapeutic and vaccine design. S trimers are extensively decorated with N-linked glycans that are important for proper folding (Rossen et al., 1998) and for modulating accessibility to host proteases and neutralizing Abs (Walls et al., 2016b, Walls et al., 2019, Xiong et al., 2018, Yang et al., 2015b). We previously characterized potent human-neutralizing Abs from rare memory B cells of individuals infected with SARS-CoV (Traggiai et al., 2004) or MERS-CoV (Corti et al., 2015) in complex with SARS-CoV S and MERS-CoV S to provide molecular-level information of the mechanism of competitive inhibition of SB attachment to the host receptor (Walls et al., 2019). The S230 anti-SARS-CoV Ab also acted by functionally mimicking receptor attachment and promoting S fusogenic conformational rearrangements through a ratcheting mechanism that elucidated the unique nature of the coronavirus membrane fusion activation (Walls et al., 2019).\nWe report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. We identified the presence of an unexpected furin cleavage site at the S1/S2 boundary of SARS-CoV-2 S, which is cleaved during biosynthesis—a novel feature setting this virus apart from SARS-CoV and SARSr-CoVs. Abrogation of this cleavage motif moderately affected SARS-CoV-2 S-mediated entry into VeroE6 or BHK cells but may contribute to expand the tropism of this virus, as reported for several highly pathogenic avian influenza viruses and pathogenic Newcastle disease virus (Klenk and Garten, 1994, Steinhauer, 1999). We determined cryoelectron microscopy (cryo-EM) structures of the SARS-CoV-2 S ectodomain trimer and reveal that it adopts multiple SB conformations that are reminiscent of previous reports on both SARS-CoV S and MERS-CoV S. Finally, we show that SARS-CoV S mouse polyclonal sera potently inhibited entry into target cells of SARS-CoV-2 S pseudotyped viruses. Collectively, these results pave the way for designing vaccines eliciting broad protection against SARS-CoV-2, SARS-CoV, and SARSr-CoV."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T1","span":{"begin":2676,"end":2691},"obj":"http://purl.obolibrary.org/obo/GO_0044409"},{"id":"T2","span":{"begin":3912,"end":3927},"obj":"http://purl.obolibrary.org/obo/GO_0061025"},{"id":"T3","span":{"begin":4326,"end":4337},"obj":"http://purl.obolibrary.org/obo/GO_0140253"},{"id":"T4","span":{"begin":4326,"end":4337},"obj":"http://purl.obolibrary.org/obo/GO_0045026"},{"id":"T5","span":{"begin":4326,"end":4337},"obj":"http://purl.obolibrary.org/obo/GO_0000768"},{"id":"T6","span":{"begin":4326,"end":4337},"obj":"http://purl.obolibrary.org/obo/GO_0000747"},{"id":"T7","span":{"begin":5388,"end":5403},"obj":"http://purl.obolibrary.org/obo/GO_0044409"},{"id":"T8","span":{"begin":5871,"end":5877},"obj":"http://purl.obolibrary.org/obo/GO_0007613"},{"id":"T9","span":{"begin":6388,"end":6403},"obj":"http://purl.obolibrary.org/obo/GO_0061025"},{"id":"T10","span":{"begin":7038,"end":7050},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T11","span":{"begin":7262,"end":7269},"obj":"http://purl.obolibrary.org/obo/GO_0009606"}],"text":"Introduction\nThree coronaviruses have crossed the species barrier to cause deadly pneumonia in humans since the beginning of the 21st century: severe acute respiratory syndrome coronavirus (SARS-CoV) (Drosten et al., 2003, Ksiazek et al., 2003), Middle-East respiratory syndrome coronavirus (Zaki et al., 2012) (MERS-CoV), and SARS-CoV-2 (Huang et al., 2020, Zhu et al., 2020). SARS-CoV emerged in the Guangdong province of China in 2002 and spread to five continents through air travel routes, infecting 8,098 people and causing 774 deaths. In 2012, MERS-CoV emerged in the Arabian Peninsula, where it remains a major public health concern, and was exported to 27 countries, infecting a total of ∼2,494 individuals and claiming 858 lives. A previously unknown coronavirus, named SARS-CoV-2, was discovered in December 2019 in Wuhan, Hubei province of China and was sequenced and isolated by January 2020 (Zhou et al., 2020, Zhu et al., 2020). SARS-CoV-2 is associated with an ongoing outbreak of atypical pneumonia (Covid-2019) that has affected over 90,000 people and killed more than 3,000 of those affected in \u003e60 countries as of March 3, 2020. On January 30, 2020, the World Health Organization declared the SARS-CoV-2 epidemic a public health emergency of international concern.\nMERS-CoV was suggested to originate from bats, but the reservoir host fueling spillover to humans is unequivocally dromedary camels (Haagmans et al., 2014, Memish et al., 2013). Both SARS-CoV and SARS-CoV-2 are closely related and originated in bats, who most likely serve as reservoir host for these two viruses (Ge et al., 2013, Hu et al., 2017, Li et al., 2005b, Yang et al., 2015a, Zhou et al., 2020). Whereas palm civets and racoon dogs have been recognized as intermediate hosts for zoonotic transmission of SARS-CoV between bats and humans (Guan et al., 2003, Kan et al., 2005, Wang et al., 2005), the SARS-CoV-2 intermediate host remains unknown. The recurrent spillovers of coronaviruses in humans along with detection of numerous coronaviruses in bats, including many SARS-related coronaviruses (SARSr-CoVs), suggest that future zoonotic transmission events may continue (Anthony et al., 2017, Ge et al., 2013, Hu et al., 2017, Li et al., 2005b, Menachery et al., 2015, Menachery et al., 2016, Yang et al., 2015a, Zhou et al., 2020). In addition to the highly pathogenic zoonotic pathogens SARS-CoV, MERS-CoV, and SARS-CoV-2, all belonging to the β-coronavirus genus, four low-pathogenicity coronaviruses are endemic in humans: HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E. To date, no therapeutics or vaccines are approved against any human-infecting coronaviruses.\nCoronavirus entry into host cells is mediated by the transmembrane spike (S) glycoprotein that forms homotrimers protruding from the viral surface (Tortorici and Veesler, 2019). S comprises two functional subunits responsible for binding to the host cell receptor (S1 subunit) and fusion of the viral and cellular membranes (S2 subunit). For many CoVs, S is cleaved at the boundary between the S1 and S2 subunits, which remain non-covalently bound in the prefusion conformation (Belouzard et al., 2009, Bosch et al., 2003, Burkard et al., 2014, Kirchdoerfer et al., 2016, Millet and Whittaker, 2014, Millet and Whittaker, 2015, Park et al., 2016, Walls et al., 2016a). The distal S1 subunit comprises the receptor-binding domain(s) and contributes to stabilization of the prefusion state of the membrane-anchored S2 subunit that contains the fusion machinery (Gui et al., 2017, Kirchdoerfer et al., 2016, Pallesen et al., 2017, Song et al., 2018, Walls et al., 2016a, Walls et al., 2017b, Yuan et al., 2017). For all CoVs, S is further cleaved by host proteases at the so-called S2′ site located immediately upstream of the fusion peptide (Madu et al., 2009, Millet and Whittaker, 2015). This cleavage has been proposed to activate the protein for membrane fusion via extensive irreversible conformational changes (Belouzard et al., 2009, Heald-Sargent and Gallagher, 2012, Millet and Whittaker, 2014, Millet and Whittaker, 2015, Park et al., 2016, Walls et al., 2017b). As a result, coronavirus entry into susceptible cells is a complex process that requires the concerted action of receptor-binding and proteolytic processing of the S protein to promote virus-cell fusion.\nDifferent coronaviruses use distinct domains within the S1 subunit to recognize a variety of attachment and entry receptors, depending on the viral species. Endemic human coronaviruses OC43 and HKU1 attach via their S domain A (SA) to 5-N-acetyl-9-O-acetyl-sialosides found on glycoproteins and glycolipids at the host cell surface to enable entry into susceptible cells (Hulswit et al., 2019, Tortorici et al., 2019, Vlasak et al., 1988). MERS-CoV S, however, uses domain A to recognize non-acetylated sialoside attachment receptors (Li et al., 2017, Park et al., 2019), which likely promote subsequent binding of domain B (SB) to the entry receptor, dipeptidyl-peptidase 4 (Lu et al., 2013, Raj et al., 2013). SARS-CoV and several SARS-related coronaviruses (SARSr-CoV) interact directly with angiotensin-converting enzyme 2 (ACE2) via SB to enter target cells (Ge et al., 2013, Kirchdoerfer et al., 2018, Li et al., 2005a, Li et al., 2003, Song et al., 2018, Yang et al., 2015a).\nAs the coronavirus S glycoprotein is surface-exposed and mediates entry into host cells, it is the main target of neutralizing antibodies (Abs) upon infection and the focus of therapeutic and vaccine design. S trimers are extensively decorated with N-linked glycans that are important for proper folding (Rossen et al., 1998) and for modulating accessibility to host proteases and neutralizing Abs (Walls et al., 2016b, Walls et al., 2019, Xiong et al., 2018, Yang et al., 2015b). We previously characterized potent human-neutralizing Abs from rare memory B cells of individuals infected with SARS-CoV (Traggiai et al., 2004) or MERS-CoV (Corti et al., 2015) in complex with SARS-CoV S and MERS-CoV S to provide molecular-level information of the mechanism of competitive inhibition of SB attachment to the host receptor (Walls et al., 2019). The S230 anti-SARS-CoV Ab also acted by functionally mimicking receptor attachment and promoting S fusogenic conformational rearrangements through a ratcheting mechanism that elucidated the unique nature of the coronavirus membrane fusion activation (Walls et al., 2019).\nWe report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. We identified the presence of an unexpected furin cleavage site at the S1/S2 boundary of SARS-CoV-2 S, which is cleaved during biosynthesis—a novel feature setting this virus apart from SARS-CoV and SARSr-CoVs. Abrogation of this cleavage motif moderately affected SARS-CoV-2 S-mediated entry into VeroE6 or BHK cells but may contribute to expand the tropism of this virus, as reported for several highly pathogenic avian influenza viruses and pathogenic Newcastle disease virus (Klenk and Garten, 1994, Steinhauer, 1999). We determined cryoelectron microscopy (cryo-EM) structures of the SARS-CoV-2 S ectodomain trimer and reveal that it adopts multiple SB conformations that are reminiscent of previous reports on both SARS-CoV S and MERS-CoV S. Finally, we show that SARS-CoV S mouse polyclonal sera potently inhibited entry into target cells of SARS-CoV-2 S pseudotyped viruses. Collectively, these results pave the way for designing vaccines eliciting broad protection against SARS-CoV-2, SARS-CoV, and SARSr-CoV."}

LitCovid-sentences

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T1","span":{"begin":82,"end":91},"obj":"Phenotype"},{"id":"T2","span":{"begin":1006,"end":1015},"obj":"Phenotype"}],"attributes":[{"id":"A1","pred":"hp_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A2","pred":"hp_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/HP_0002090"}],"text":"Introduction\nThree coronaviruses have crossed the species barrier to cause deadly pneumonia in humans since the beginning of the 21st century: severe acute respiratory syndrome coronavirus (SARS-CoV) (Drosten et al., 2003, Ksiazek et al., 2003), Middle-East respiratory syndrome coronavirus (Zaki et al., 2012) (MERS-CoV), and SARS-CoV-2 (Huang et al., 2020, Zhu et al., 2020). SARS-CoV emerged in the Guangdong province of China in 2002 and spread to five continents through air travel routes, infecting 8,098 people and causing 774 deaths. In 2012, MERS-CoV emerged in the Arabian Peninsula, where it remains a major public health concern, and was exported to 27 countries, infecting a total of ∼2,494 individuals and claiming 858 lives. A previously unknown coronavirus, named SARS-CoV-2, was discovered in December 2019 in Wuhan, Hubei province of China and was sequenced and isolated by January 2020 (Zhou et al., 2020, Zhu et al., 2020). SARS-CoV-2 is associated with an ongoing outbreak of atypical pneumonia (Covid-2019) that has affected over 90,000 people and killed more than 3,000 of those affected in \u003e60 countries as of March 3, 2020. On January 30, 2020, the World Health Organization declared the SARS-CoV-2 epidemic a public health emergency of international concern.\nMERS-CoV was suggested to originate from bats, but the reservoir host fueling spillover to humans is unequivocally dromedary camels (Haagmans et al., 2014, Memish et al., 2013). Both SARS-CoV and SARS-CoV-2 are closely related and originated in bats, who most likely serve as reservoir host for these two viruses (Ge et al., 2013, Hu et al., 2017, Li et al., 2005b, Yang et al., 2015a, Zhou et al., 2020). Whereas palm civets and racoon dogs have been recognized as intermediate hosts for zoonotic transmission of SARS-CoV between bats and humans (Guan et al., 2003, Kan et al., 2005, Wang et al., 2005), the SARS-CoV-2 intermediate host remains unknown. The recurrent spillovers of coronaviruses in humans along with detection of numerous coronaviruses in bats, including many SARS-related coronaviruses (SARSr-CoVs), suggest that future zoonotic transmission events may continue (Anthony et al., 2017, Ge et al., 2013, Hu et al., 2017, Li et al., 2005b, Menachery et al., 2015, Menachery et al., 2016, Yang et al., 2015a, Zhou et al., 2020). In addition to the highly pathogenic zoonotic pathogens SARS-CoV, MERS-CoV, and SARS-CoV-2, all belonging to the β-coronavirus genus, four low-pathogenicity coronaviruses are endemic in humans: HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E. To date, no therapeutics or vaccines are approved against any human-infecting coronaviruses.\nCoronavirus entry into host cells is mediated by the transmembrane spike (S) glycoprotein that forms homotrimers protruding from the viral surface (Tortorici and Veesler, 2019). S comprises two functional subunits responsible for binding to the host cell receptor (S1 subunit) and fusion of the viral and cellular membranes (S2 subunit). For many CoVs, S is cleaved at the boundary between the S1 and S2 subunits, which remain non-covalently bound in the prefusion conformation (Belouzard et al., 2009, Bosch et al., 2003, Burkard et al., 2014, Kirchdoerfer et al., 2016, Millet and Whittaker, 2014, Millet and Whittaker, 2015, Park et al., 2016, Walls et al., 2016a). The distal S1 subunit comprises the receptor-binding domain(s) and contributes to stabilization of the prefusion state of the membrane-anchored S2 subunit that contains the fusion machinery (Gui et al., 2017, Kirchdoerfer et al., 2016, Pallesen et al., 2017, Song et al., 2018, Walls et al., 2016a, Walls et al., 2017b, Yuan et al., 2017). For all CoVs, S is further cleaved by host proteases at the so-called S2′ site located immediately upstream of the fusion peptide (Madu et al., 2009, Millet and Whittaker, 2015). This cleavage has been proposed to activate the protein for membrane fusion via extensive irreversible conformational changes (Belouzard et al., 2009, Heald-Sargent and Gallagher, 2012, Millet and Whittaker, 2014, Millet and Whittaker, 2015, Park et al., 2016, Walls et al., 2017b). As a result, coronavirus entry into susceptible cells is a complex process that requires the concerted action of receptor-binding and proteolytic processing of the S protein to promote virus-cell fusion.\nDifferent coronaviruses use distinct domains within the S1 subunit to recognize a variety of attachment and entry receptors, depending on the viral species. Endemic human coronaviruses OC43 and HKU1 attach via their S domain A (SA) to 5-N-acetyl-9-O-acetyl-sialosides found on glycoproteins and glycolipids at the host cell surface to enable entry into susceptible cells (Hulswit et al., 2019, Tortorici et al., 2019, Vlasak et al., 1988). MERS-CoV S, however, uses domain A to recognize non-acetylated sialoside attachment receptors (Li et al., 2017, Park et al., 2019), which likely promote subsequent binding of domain B (SB) to the entry receptor, dipeptidyl-peptidase 4 (Lu et al., 2013, Raj et al., 2013). SARS-CoV and several SARS-related coronaviruses (SARSr-CoV) interact directly with angiotensin-converting enzyme 2 (ACE2) via SB to enter target cells (Ge et al., 2013, Kirchdoerfer et al., 2018, Li et al., 2005a, Li et al., 2003, Song et al., 2018, Yang et al., 2015a).\nAs the coronavirus S glycoprotein is surface-exposed and mediates entry into host cells, it is the main target of neutralizing antibodies (Abs) upon infection and the focus of therapeutic and vaccine design. S trimers are extensively decorated with N-linked glycans that are important for proper folding (Rossen et al., 1998) and for modulating accessibility to host proteases and neutralizing Abs (Walls et al., 2016b, Walls et al., 2019, Xiong et al., 2018, Yang et al., 2015b). We previously characterized potent human-neutralizing Abs from rare memory B cells of individuals infected with SARS-CoV (Traggiai et al., 2004) or MERS-CoV (Corti et al., 2015) in complex with SARS-CoV S and MERS-CoV S to provide molecular-level information of the mechanism of competitive inhibition of SB attachment to the host receptor (Walls et al., 2019). The S230 anti-SARS-CoV Ab also acted by functionally mimicking receptor attachment and promoting S fusogenic conformational rearrangements through a ratcheting mechanism that elucidated the unique nature of the coronavirus membrane fusion activation (Walls et al., 2019).\nWe report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. We identified the presence of an unexpected furin cleavage site at the S1/S2 boundary of SARS-CoV-2 S, which is cleaved during biosynthesis—a novel feature setting this virus apart from SARS-CoV and SARSr-CoVs. Abrogation of this cleavage motif moderately affected SARS-CoV-2 S-mediated entry into VeroE6 or BHK cells but may contribute to expand the tropism of this virus, as reported for several highly pathogenic avian influenza viruses and pathogenic Newcastle disease virus (Klenk and Garten, 1994, Steinhauer, 1999). We determined cryoelectron microscopy (cryo-EM) structures of the SARS-CoV-2 S ectodomain trimer and reveal that it adopts multiple SB conformations that are reminiscent of previous reports on both SARS-CoV S and MERS-CoV S. Finally, we show that SARS-CoV S mouse polyclonal sera potently inhibited entry into target cells of SARS-CoV-2 S pseudotyped viruses. Collectively, these results pave the way for designing vaccines eliciting broad protection against SARS-CoV-2, SARS-CoV, and SARSr-CoV."}

2_test

PMC:7102599 / 1798-9727 JSONTXT

Annnotations TAB JSON ListView MergeView

PMC:7102599 / 1798-9727 JSON TXT