Cell host & microbe
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Cell host & microbe · Jan 2021
Randomized Controlled TrialD614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. ⋯ Negative stain electron microscopy revealed a higher percentage of the 1-RBD "up" conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.
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Microbes expertly manipulate hosts to their advantage, but few completely escape detection. In this issue of Cell Host & Microbe, Takaki et al. (2021) describe how Schistosoma mansoni eggs choreograph macrophage behaviors to promote efficient transmission of mature eggs, while immature eggs remain safely hidden in plain sight.
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Cell host & microbe · Nov 2020
Comment ReviewACTIVating Resources for the COVID-19 Pandemic: In Vivo Models for Vaccines and Therapeutics.
The Preclinical Working Group of Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership spearheaded by the National Institutes of Health, has been charged with identifying, prioritizing, and communicating SARS-CoV-2 preclinical resources. Reviewing SARS-CoV-2 animal model data facilitates standardization and harmonization and informs knowledge gaps and prioritization of limited resources. To date, mouse, hamster, ferret, guinea pig, and non-human primates have been investigated. ⋯ More severe disease develops in a few models, some associated with advanced age, a risk factor for human disease. This review provides a snapshot that recommends the suitability of models for testing vaccines and therapeutics, which may evolve as our understanding of COVID-19 disease biology improves. COVID-19 is a complex disease, and individual models recapitulate certain aspects of disease; therefore, the coordination and assessment of animal models is imperative.
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Cell host & microbe · Oct 2020
Human B Cell Clonal Expansion and Convergent Antibody Responses to SARS-CoV-2.
B cells are critical for the production of antibodies and protective immunity to viruses. Here we show that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) display early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. ⋯ Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and SARS-CoV.
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There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. ⋯ Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.