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  • 1
    Online Resource
    Online Resource
    Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity
    American Society for Microbiology ; 2023
    In:  Journal of Virology Vol. 97, No. 7 ( 2023-07-27)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 97, No. 7 ( 2023-07-27)
    Abstract: Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, we report the crystal structure of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) in complex with MAb WRAIR-2063, a moderate-potency neutralizing antibody with exceptional sarbecovirus breadth, that targets the highly conserved cryptic class V epitope. This epitope overlaps substantially with the spike protein N-terminal domain (NTD) -interacting region and is exposed only when the spike is in the open conformation, with one or more RBDs accessible. WRAIR-2063 binds the RBD of SARS-CoV-2 WA-1, all variants of concern (VoCs), and clade 1 to 4 sarbecoviruses with high affinity, demonstrating the conservation of this epitope and potential resiliency against variation. We compare structural features of additional class V antibodies with their reported neutralization capacity to further explore the utility of the class V epitope as a pan-sarbecovirus vaccine and therapeutic target. IMPORTANCE Characterization of MAbs against SARS-CoV-2, elicited through vaccination or natural infection, has provided vital immunotherapeutic options for curbing the COVID-19 pandemic and has supplied critical insights into SARS-CoV-2 escape, transmissibility, and mechanisms of viral inactivation. Neutralizing MAbs that target the RBD but do not block ACE2 binding are of particular interest because the epitopes are well conserved within sarbecoviruses and MAbs targeting this area demonstrate cross-reactivity. The class V RBD-targeted MAbs localize to an invariant site of vulnerability, provide a range of neutralization potency, and exhibit considerable breadth against divergent sarbecoviruses, with implications for vaccine and therapeutic development.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.01596-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 1495529-5
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  • 2
    Online Resource
    Online Resource
    Table_1.xlsx
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-5-31)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-5-31)
    Abstract: Fc-mediated virus entry has been observed for many viruses, but the characterization of this activity in convalescent plasma against SARS-CoV-2 Variants of Concern (VOC) is undefined. In this study, we evaluated Fc-mediated viral entry (FVE) on FcγRIIa-expressing HEK293 cells in the presence of SARS-CoV-2 convalescent plasma and compared it with SARS-CoV-2 pseudovirus neutralization using ACE2-expressing HEK293 cells. The plasma were collected early in the pandemic from 39 individuals. We observed both neutralization and FVE against the infecting Washington SARS-CoV-2 strain for 31% of plasmas, neutralization, but not FVE for 61% of plasmas, and no neutralization or FVE for 8% of plasmas. Neutralization titer correlated significantly with the plasma dilution at which maximum FVE was observed, indicating Fc-mediated uptake peaked as neutralization potency waned. While total Spike-specific plasma IgG levels were similar between plasma that mediated FVE and those that did not, Spike-specific plasma IgM levels were significantly higher in plasma that did not mediate FVE. Plasma neutralization titers against the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) VOC were significantly lower than titers against the Washington strain, while plasma FVE activity against the VOC was either higher or similar. This is the first report to demonstrate a functional shift in convalescent plasma antibodies from neutralizing and FVE-mediating against the earlier Washington strain, to an activity mediating only FVE and no neutralization activity against the emerging VOC, specifically the Beta (B.1.351) and Gamma (P.1) VOC. It will be important to determine the in vivo relevance of these findings.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.901217
    DOI: 10.3389/fimmu.2022.901217.s001
    DOI: 10.3389/fimmu.2022.901217.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 3
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    Online Resource
    Image_1.TIF
    Frontiers Media SA ; 2022
    In:  Frontiers in Neural Circuits Vol. 16 ( 2022-4-7)
    Details
    In: Frontiers in Neural Circuits, Frontiers Media SA, Vol. 16 ( 2022-4-7)
    Abstract: The lateral cortex of the inferior colliculus (LCIC) is a multimodal subdivision of the midbrain inferior colliculus (IC) that plays a key role in sensory integration. The LCIC is compartmentally-organized, exhibiting a series of discontinuous patches or modules surrounded by an extramodular matrix. In adult mice, somatosensory afferents target LCIC modular zones, while auditory afferents terminate throughout the encompassing matrix. Recently, we defined an early LCIC critical period (birth: postnatal day 0 to P12) based upon the concurrent emergence of its neurochemical compartments (modules: glutamic acid decarboxylase, GAD+; matrix: calretinin, CR+), matching Eph-ephrin guidance patterns, and specificity of auditory inputs for its matrix. Currently lacking are analogous experiments that address somatosensory afferent shaping and the construction of discrete LCIC multisensory maps. Combining living slice tract-tracing and immunocytochemical approaches in a developmental series of GAD67-GFP knock-in mice, the present study characterizes: (1) the targeting of somatosensory terminals for emerging LCIC modular fields; and (2) the relative separation of somatosensory and auditory inputs over the course of its established critical period. Results indicate a similar time course and progression of LCIC projection shaping for both somatosensory (corticocollicular) and auditory (intracollicular) inputs. While somewhat sparse and intermingling at birth, modality-specific projection patterns soon emerge (P4–P8), coincident with peak guidance expression and the appearance of LCIC compartments. By P12, an adult-like arrangement is in place, with fully segregated multimodal afferent arrays. Quantitative measures confirm increasingly distinct input maps, exhibiting less projection overlap with age. Potential mechanisms whereby multisensory LCIC afferent systems recognize and interface with its emerging modular-matrix framework are discussed.
    Type of Medium: Online Resource
    ISSN: 1662-5110
    URL: Article
    URL: Article
    DOI: 10.3389/fncir.2022.882485
    DOI: 10.3389/fncir.2022.882485.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2452968-0
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