Live Imaging of SARS-CoV-2 Infection in Mice Reveals Neutralizing Antibodies Require Fc Function for Optimal Efficacy

Ullah, Irfan; Prévost, Jérémie; Ladinsky, Mark S.; Stone, Helen; Lu, Maolin; Anand, Sai Priya; Beaudoin-Bussières, Guillaume; Benlarbi, Mehdi; Ding, Shilei; Gasser, Romain; Fink, Corby; Chen, Yaozong; Tauzin, Alexandra; Goyette, Guillaume; Bourassa, Catherine; Medjahed, Halima; Mack, Matthias; Chung, Ki-Seok; Wilen, Craig B.; Dekaban, Gregory A.; Dikeakos, Jimmy D.; Bruce, Emily A.; Kaufmann, Daniel E.; Stamatatos, Leonidas; McGuire, Andrew T.; Richard, Jonathan; Pazgier, Marzena; Björkman, Pamela J.; Mothes, Walther; Uchil, Pradeep D.; Kumar, Priti

doi:10.2139/ssrn.3817810

Cited by 3 publications

(2 citation statements)

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“…SARS-CoV-1 also showed dissemination to the brain ( 48 ). A recent study showed the ubiquity of SARS-CoV-2 infection in mice and delineated the rapid time course of neuroinvasion ( 49 ). This study also discovered that the Fc portion of antibodies, not just the binding regions, was important for the anti-viral response ( 49 ).…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

“…A recent study showed the ubiquity of SARS-CoV-2 infection in mice and delineated the rapid time course of neuroinvasion ( 49 ). This study also discovered that the Fc portion of antibodies, not just the binding regions, was important for the anti-viral response ( 49 ). This highlighted that NK cells, macrophages, and neutrophils play a role in clearing the virus dependent on FcR binding involved in antibody-dependent cytotoxicity and phagocytosis and emphasised the consideration needed for the Fc region when developing effective therapeutic antibodies.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

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Immune-Mediated Mechanisms of COVID-19 Neuropathology

2022

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Although SARS-CoV-2 causes a respiratory viral infection, there is a large incidence of neurological complications occurring in COVID-19 patients. These range from headaches and loss of smell to encephalitis and strokes. Little is known about the likely diverse mechanisms causing these pathologies and there is a dire need to understand how to prevent and treat them. This review explores recent research from the perspective of investigating how the immune system could play a role in neurological complications, including cytokines, blood biomarkers, immune cells, and autoantibodies. We also discuss lessons learnt from animal models. Overall, we highlight two key points that have emerged from increasing evidence: (1) SARS-CoV-2 does not invade the brain in the majority of cases and so the associated neurological complications might arise from indirect effects, such as immune activation (2) although the immune system plays a critical role in controlling the virus, its dysregulation can cause pathology.

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Section: Lessons From Animal Modelsmentioning

confidence: 99%

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Immune-Mediated Mechanisms of COVID-19 Neuropathology

2022

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Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern

Mothes

Chen

et al. 2021

Preprint

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Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here we elucidate the structural basis and mode of action for two potent SARS-CoV-2 Spike (S) neutralizing monoclonal antibodies CV3-1 and CV3-25 that remained effective against emerging variants of concern in vitro and in vivo. CV3-1 bound to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the RBD-up position and triggered potent shedding of the S1 subunit. In contrast, CV3-25 inhibited membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among beta-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

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A public antibody class recognizes a novel S2 epitope exposed on open conformations of SARS-CoV-2 spike

Claireaux

Caniels

Gast

et al. 2021

Preprint

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Delineating the origins and properties of antibodies elicited by SARS-CoV-2 infection and vaccination is critical for understanding their benefits and potential shortcomings. Therefore, we investigated the SARS-CoV-2 spike (S)-reactive B cell repertoire in unexposed individuals by flow cytometry and single-cell sequencing. We found that ∼82% of SARS-CoV-2 S-reactive B cells show a naive phenotype, which represents an unusually high fraction of total human naive B cells (∼0.1%). Approximately 10% of these naive S-reactive B cells shared an IGHV1-69/IGKV3-11 B cell receptor pairing, an enrichment of 18-fold compared to the complete naive repertoire. A proportion of memory B cells, comprising switched (∼0.05%) and unswitched B cells (∼0.04%), was also reactive with S and some of these cells were reactive with ADAMTS13, which is associated with thrombotic thrombocytopenia. Following SARS-CoV-2 infection, we report an average 37-fold enrichment of IGHV1-69/IGKV3-11 B cell receptor pairing in the S-reactive memory B cells compared to the unselected memory repertoire. This class of B cells targets a previously undefined non-neutralizing epitope on the S2 subunit that becomes exposed on S proteins used in approved vaccines when they transition away from the native pre-fusion state because of instability. These findings can help guide the improvement of SARS-CoV-2 vaccines.

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Live Imaging of SARS-CoV-2 Infection in Mice Reveals Neutralizing Antibodies Require Fc Function for Optimal Efficacy

Cited by 3 publications

References 45 publications

Immune-Mediated Mechanisms of COVID-19 Neuropathology

Immune-Mediated Mechanisms of COVID-19 Neuropathology

Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern

A public antibody class recognizes a novel S2 epitope exposed on open conformations of SARS-CoV-2 spike

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