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抗伤寒毒素单域抗体的制备及其对 PltB 和 CdtB 亚单位的中和作用。

Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits.

机构信息

Department of Microbiology and Immunology, Cornell Universitygrid.5386.8, Ithaca, New York, USA.

Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, New York, USA.

出版信息

Infect Immun. 2022 Feb 17;90(2):e0051521. doi: 10.1128/IAI.00515-21. Epub 2021 Dec 13.

DOI:10.1128/IAI.00515-21
PMID:34898253
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8852740/
Abstract

Typhoid toxin is secreted by the typhoid fever-causing bacterial pathogen Salmonella enterica serovar Typhi and has tropism for immune cells and brain endothelial cells. Here, we generated a camelid single-domain antibody (VHH) library from typhoid toxoid-immunized alpacas and identified 41 VHHs selected on the glycan receptor-binding PltB and nuclease CdtB. VHHs exhibiting potent neutralizing activities from each sequence-based family were epitope binned via competition enzyme-linked immunosorbent assays (ELISAs), leading to 6 distinct VHHs, 2 anti-PltBs (T2E7 and T2G9), and 4 anti-CdtB VHHs (T4C4, T4C12, T4E5, and T4E8), whose neutralizing activities and associated toxin-neutralizing mechanisms were investigated. We found that T2E7, T2G9, and T4E5 effectively neutralized typhoid toxin , as demonstrated by 100% survival of mice administered a lethal dose of typhoid toxin and with little to no typhoid toxin-mediated upper motor function defect. Cumulatively, these results highlight the potential of the compact antibodies to neutralize typhoid toxin by targeting the glycan-binding and/or nuclease subunits.

摘要

伤寒毒素由伤寒致病细菌病原体沙门氏菌肠亚种 Typhi 分泌，对免疫细胞和脑内皮细胞具有亲嗜性。在这里，我们从伤寒类毒素免疫的羊驼中生成了一个骆驼科单域抗体 (VHH) 文库，并在聚糖受体结合 PltB 和核酸酶 CdtB 上选择了 41 个 VHH。来自每个基于序列的家族的具有强大中和活性的 VHH 通过竞争酶联免疫吸附测定 (ELISA) 进行表位分组，导致 6 种不同的 VHH，2 种抗 PltB (T2E7 和 T2G9) 和 4 种抗 CdtB VHH (T4C4、T4C12、T4E5 和 T4E8)，研究了它们的中和活性和相关毒素中和机制。我们发现 T2E7、T2G9 和 T4E5 有效地中和了伤寒毒素，这表现为给予致死剂量伤寒毒素的小鼠存活率为 100%，并且伤寒毒素介导的上运动功能缺陷很少或没有。总的来说，这些结果突出了这些紧凑型抗体通过靶向聚糖结合和/或核酸酶亚基来中和伤寒毒素的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/c1f0134c9cd2/iai.00515-21-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/4bb0df09e5a8/iai.00515-21-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/df9dcee398fa/iai.00515-21-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/7012b26e1d65/iai.00515-21-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/4f7a9a76949b/iai.00515-21-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/c1f0134c9cd2/iai.00515-21-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/4bb0df09e5a8/iai.00515-21-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/df9dcee398fa/iai.00515-21-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/7012b26e1d65/iai.00515-21-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/4f7a9a76949b/iai.00515-21-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81bc/8852740/c1f0134c9cd2/iai.00515-21-f005.jpg

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