On the molecular mechanism of SARS-CoV-2 retention in the upper respiratory tract
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Abstract
Cell surface receptor engagement is a critical aspect of viral infection. At low pH, binding of SARS-CoV and its ACE2 receptor has a tight interaction that catalyzes the fusion of the spike and endosomal membranes followed by genome release. Largely overlooked has been the role of neutral pH in the respiratory tract, where we find that SARS-CoV stabilizes a transition state that enhances the off-rate from its receptor. An alternative pH-switch is found in CoV-2-like coronaviruses of tropical pangolins, but with a reversed phenotype where the tight interaction with ACE2 is at neutral pH. We show that a single point mutation in pangolin-CoV, unique to CoV-2, that deletes the last His residue in their receptor binding domain perpetuates this tight interaction independent of pH. This tight bond, not present in previous respiratory syndromes, implies that CoV-2 stays bound to the highly expressed ACE2 receptors in the nasal cavity about 100 times longer than CoV. This finding supports the unfamiliar pathology of CoV-2, observed virus retention in upper respiratory tract 1 , longer incubation times and extended periods of shedding. Implications to combat pandemics that, like SARS-CoV-2, export evolutionarily successful strains via higher transmission rates due to retention in nasal epithelium and their evolutionary origin are discussed.
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SciScore for 10.1101/2020.07.29.227389: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources The RBD from 2DD8 (bound to neutralizing antibody) was chosen instead of that in PDB ID 2AJF (bound to ACE2) as a starting structure as it includes otherwise missing portions of the domain. ACE2suggested: NoneSoftware and Algorithms Sentences Resources 2 Molecular dynamics simulations (MDs) were carried out with pmemd.cuda from AMBER183–5 using AMBER ff14SB force field6 and Generalized Amber Force Field (GAFF). AMBERsuggested: (AMBER, RRID:SCR_016151)9 Homology models of RBD of pangolin-CoV were done making point mutations using PyMOL in CoV2 RBD from PDB 6LZG. PyMOLsuggested: (PyMOL, RRID:SCR_000305)Results…
SciScore for 10.1101/2020.07.29.227389: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources The RBD from 2DD8 (bound to neutralizing antibody) was chosen instead of that in PDB ID 2AJF (bound to ACE2) as a starting structure as it includes otherwise missing portions of the domain. ACE2suggested: NoneSoftware and Algorithms Sentences Resources 2 Molecular dynamics simulations (MDs) were carried out with pmemd.cuda from AMBER183–5 using AMBER ff14SB force field6 and Generalized Amber Force Field (GAFF). AMBERsuggested: (AMBER, RRID:SCR_016151)9 Homology models of RBD of pangolin-CoV were done making point mutations using PyMOL in CoV2 RBD from PDB 6LZG. PyMOLsuggested: (PyMOL, RRID:SCR_000305)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.07.29.227389: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources The RBD from 2DD8 (bound to neutralizing antibody) was chosen instead of that in PDB ID 2AJF (bound to ACE2) as a starting structure as it includes otherwise missing portions of the domain. ACE2suggested: NoneSoftware and Algorithms Sentences Resources Hence, one would expect that both CoV1 and CoV2 interaction with ACE2 to be similar. CoV1suggested: None2 Molecular dynamics simulations (MDs) were carried out with pmemd.cuda from AMBER183-5 using AMBER ff14SB force field6 and … SciScore for 10.1101/2020.07.29.227389: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources The RBD from 2DD8 (bound to neutralizing antibody) was chosen instead of that in PDB ID 2AJF (bound to ACE2) as a starting structure as it includes otherwise missing portions of the domain. ACE2suggested: NoneSoftware and Algorithms Sentences Resources Hence, one would expect that both CoV1 and CoV2 interaction with ACE2 to be similar. CoV1suggested: None2 Molecular dynamics simulations (MDs) were carried out with pmemd.cuda from AMBER183-5 using AMBER ff14SB force field6 and Generalized Amber Force Field (GAFF). AMBERsuggested: (AMBER, SCR_016151)9 Homology models of RBD of pangolin-CoV were done making point mutations using PyMOL in CoV2 RBD from PDB 6LZG. PyMOLsuggested: (PyMOL, SCR_000305)Data from additional tools added to each annotation on a weekly basis.
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