IgA MAb blocks SARS-CoV-2 Spike-ACE2 interaction providing mucosal immunity

Ejemel, Monir; Qi, Liqun; Hou, Shurong; Schiller, Zachary A.; Wallace, Aaron; Amcheslavsky, Alla; Yilmaz, Neşe Kurt; Toomey, Jacqueline R.; Schneider, Ryan; Close, Brianna J.; Chen, Da Yuan; Conway, Hashan L.; Saeed, Mohsan; Cavacini, Lisa A.; Klempner, Mark S.; Schiffer, Celia A.; Wang, Yang

doi:10.1101/2020.05.15.096719

Cited by 24 publications

(31 citation statements)

References 36 publications

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“…In agreement with previous studies, there was a skewing of the repertoire in the response to SARS-CoV-2 infection, with an increased use of certain V genes, an increase in the proportion of antibodies with longer CDRH3s, and an altered isotype subclass distribution 14 . The significantly increased usage of IGHA1 observed in the COVID-19 patients is in line with mucosal responses, where the longer hinge in IGHA1 compared to IGHA2 may offer advantages in antigen recognition by allowing higher avidity bivalent interactions with distantly spaced antigens 25 .…”

Section: Discussionmentioning

confidence: 52%

Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Galson¹,

Schaetzle²,

Bashford-Rogers

et al. 2020

Preprint

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Deep sequencing of B cell receptor (BCR) heavy chains from a cohort of 19 COVID-19 patients from the UK reveals a stereotypical naive immune response to SARS-CoV-2 which is consistent across patients and may be a positive indicator of disease outcome. Clonal expansion of the B cell memory response is also observed and may be the result of memory bystander effects. There was a strong convergent sequence signature across patients, and we identified 777 clonotypes convergent between at least four of the COVID-19 patients, but not present in healthy controls. A subset of the convergent clonotypes were homologous to known SARS and SARS-CoV-2 spike protein neutralising antibodies. Convergence was also demonstrated across wide geographies by comparison of data sets between patients from UK, USA and China, further validating the disease association and consistency of the stereotypical immune response even at the sequence level. These convergent clonotypes provide a resource to identify potential therapeutic and prophylactic antibodies and demonstrate the potential of BCR profiling as a tool to help understand and predict positive patient responses.

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Section: Discussionmentioning

confidence: 52%

Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Galson¹,

Schaetzle²,

Bashford-Rogers

et al. 2020

Preprint

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“…Since milks of cow and goat contain much lower concentration (0.02-0.2mg/mL) of LF than human breastmilk (1-7mg/ml), the findings that milks of cow and goat inhibited the infectivity of SARS-CoV-2 also suggest that LF is not the active component to inactivate SARS-CoV-2 (21). Besides LF, specific immunoglobulins are also important for the host defense system (18). It was reported that IgA antibody from the recovery patients blocks the interaction of SARS-CoV-2 and ACE2 (18).…”

Section: Discussionmentioning

confidence: 99%

“…Besides LF, specific immunoglobulins are also important for the host defense system (18). It was reported that IgA antibody from the recovery patients blocks the interaction of SARS-CoV-2 and ACE2 (18). As the human breastmilk samples were collected before the emergence of COVID-19, the breastmilk donors should have not been infected with SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

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The effect of whey protein on viral infection and replication of SARS-CoV-2 and pangolin coronavirus in vitro

Fan

Luo

Hong

et al. 2020

Preprint

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Since the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human breastmilk, little is known about the antiviral property of human breastmilk to SARS-CoV-2 and its related pangolin coronavirus (GX_P2V). Here we present for the first time that whey protein from human breastmilk effectively inhibited both SARS-CoV-2 and GX_P2V by blocking viral attachment, entry and even post-entry viral replication. Moreover, human whey protein inhibited infectious virus production proved by the plaque assay. We found that whey protein from different species such as cow and goat also showed anti-coronavirus properties. And commercial bovine milk also showed similar activity. Interestingly, the main antimicrobial components of breastmilk, such as Lactoferrin and IgA antibody, showed limited anti-coronavirus activity, indicating that other factors of breastmilk may play the important anti-coronavirus role. Taken together, we reported that whey protein inhibits SARS-CoV-2 and its related virus of GX_P2V. These results rule out whey protein as a direct-acting inhibitor of SARS-CoV-2 and GX_P2V infection and replication and further investigation of its molecular mechanism of action in the context of COVID-19.

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“…74 In this respect, several SARS-CoV-2 antibodies targeting the S protein have been identified (Table S11). 61,62,[64][65][66][67][68][75][76][77][78][79] The majority of these antibodies recognizes epitopes on the RBD, while only a few have been shown to address other antigenic regions within the NTD and CD ( Figure S12). Among the RBD antibodies, B38 interacts with the RBM at the RBD/ACE2 interface, 64 whereas S309 and CR3022 target the side/bottom part of the RBD.…”

Section: Glycan Shield Of the Receptor Binding Domainmentioning

confidence: 99%

Beyond Shielding: The Roles of Glycans in SARS-CoV-2 Spike Protein

Casalino

Gaieb

Goldsmith

et al. 2020

Preprint

314

564

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The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 7,000,000 infections and 400,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates the host cell entry by binding to the angiotensinconverting enzyme 2 (ACE2). In the context of vaccine design, similar to many other viruses, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the glycan shield and the protein structure, stability, and dynamics. End-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of SARS-CoV-2 S protein, which can be harnessed for vaccine development. In addition, a dynamic analysis of the main antibody epitopes is provided. Finally, beyond shielding, a possible structural role of N-glycans at N165 and N234 is hypothesized to modulate and stabilize the conformational dynamics of the spike's receptor binding domain, which is responsible for ACE2 recognition. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, which may be exploited by therapeutic efforts targeting this essential molecular machine. Glycan Shield of the Receptor Binding DomainAs discussed in the previous section, the glycan shield plays a critical role in hiding the S protein surface from molecular recognition. However, to effectively function, the spike needs to recognize and bind to ACE2 receptors as the primary host cell infection route. For this reason, the RBM must become fully exposed and accessible. 48 In this scenario, the glycan shield works in concert with a large conformational change that allows the RBD to emerge above the N-glycan coverage. Here, we quantify the ASA of the RBM within RBD-A, corresponding to the RBD/ACE2-interacting region (residues 400-508), at various probe radii in both the Open and Closed systems (Figures 3A and 3D, full data in Tables S4-S6.). As expected, the ASA plots show a significant difference between the "down" (Closed) and "up" (Open) RBD conformations, with the RBM area covered by glycans being remarkably larger in the former. When RBD-A is in the "up" conformation, its RBM shows an average (across all radii) of only ~9% surface area covered by glycans, compared with ~35% in the Closed system (Figures 3A and 3D). This difference is further amplified when considering a larger probe radius of 15 Å, with a maximum of 11% and 46% for Open and Closed, respectively. Interestingly, for smaller probes (1.4-3 Å) the shielding becomes weak in both systems, with an average of 6% and 16% for Open and Closed, respectively.Note that the RBD regio...

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IgA MAb blocks SARS-CoV-2 Spike-ACE2 interaction providing mucosal immunity

Cited by 24 publications

References 36 publications

Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

The effect of whey protein on viral infection and replication of SARS-CoV-2 and pangolin coronavirus in vitro

Beyond Shielding: The Roles of Glycans in SARS-CoV-2 Spike Protein

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