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Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis.

ABSTRACT: Mycobacterium tuberculosis (Mtb) exposure drives antibody responses, but whether patients with active tuberculosis elicit protective antibodies, and against which antigens, is still unclear. Here we generate monoclonal antibodies from memory B cells of one patient to investigate the B cell responses during active infection. The antibodies, members of four distinct B cell clones, are directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163 reduce Mycobacterium bovis-BCG and Mtb levels in an ex vivo human whole blood growth inhibition assay in an FcR-dependent manner; meanwhile, germline versions of p4-36 and p4-163 do not bind Mtb. Crystal structures of p4-36 and p4-170, complexed to PstS1, are determined at 2.1?Å and 2.4?Å resolution, respectively, to reveal two distinctive PstS1 epitopes. Lastly, a prophylactic p4-36 and p4-163 treatment in Mtb-infected Balb/c mice reduces bacterial lung burden by 50%. Our study shows that inhibitory anti-PstS1 B cell responses arise during active tuberculosis.

SUBMITTER: Watson A

PROVIDER: S-EPMC7840946 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis.

Watson Avia A Li Hao H Ma Bingting B Weiss Ronen R Bendayan Daniele D Abramovitz Lilach L Ben-Shalom Noam N Mor Michael M Pinko Erica E Bar Oz Michal M Wang Zhenqi Z Du Fengjiao F Lu Yu Y Rybniker Jan J Dahan Rony R Huang Hairong H Barkan Daniel D Xiang Ye Y Javid Babak B Freund Natalia T NT

Nature communications 20210127 1

Mycobacterium tuberculosis (Mtb) exposure drives antibody responses, but whether patients with active tuberculosis elicit protective antibodies, and against which antigens, is still unclear. Here we generate monoclonal antibodies from memory B cells of one patient to investigate the B cell responses during active infection. The antibodies, members of four distinct B cell clones, are directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163 reduce Mycobacterium bov ...[more]

PMID: 33504803

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Project description:Accumulating evidence indicates that antibodies can protect against some intracellular pathogens. Mycobacterium bovis is an intracellular bacterium, and its cell wall (CW) is essential for its virulence and survival. However, the questions of whether antibodies play a protective role in immunity against M. bovis infection and what effects antibodies specific to the CW of M. bovis have still remain unclear. Here, we report that antibodies targeting the CW of an isolated pathogenic M. bovis strain and that of an attenuated bacillus Calmette-Guérin (BCG) strain could induce protection against virulent M. bovis infection in vitro and in vivo. Further research found that the antibody-induced protection was mainly achieved by promoting Fc gamma receptor (FcγR)-mediated phagocytosis, inhibiting bacterial intracellular growth, and enhancing the fusion of phagosomes and lysosomes, and it also depended on T cells for its efficacy. Additionally, we analyzed and characterized the B-cell receptor (BCR) repertoires of CW-immunized mice via next-generation sequencing. CW immunization stimulated BCR changes in the complementarity determining region 3 (CDR3) isotype distribution, gene usage, and somatic hypermutation. Overall, our study validates the idea that antibodies targeting the CW induce protection against virulent M. bovis infection. This study highlights the importance of antibodies targeting the CW in the defense against tuberculosis. IMPORTANCE M. bovis is the causative agent of animal tuberculosis (TB) and human TB. Research on M. bovis is of great public health significance. Currently, TB vaccines are mainly aimed at eliciting protection by enhancement of cell-mediated immunity, and there are few studies on protective antibodies. This is the first report of protective antibodies against M. bovis infection, and the antibodies had both preventive and even therapeutic effects in an M. bovis infection mouse model. Additionally, we reveal the relationship between CDR3 gene diversity and the immune characteristics of the antibodies. These results will provide valuable advice for the rational development of TB vaccines.

Dataset Information

Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis.

Publications

Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis.

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