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

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 tuberculosis. 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 FcγR-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, revealing distinctive PstS1 epitopes. Lastly, prophylactic p4-36 and p4-163 treatment in Mtb-infected Balb/c mice reduces bacterial lung burden. Our study shows that inhibitory anti-PstS1 B cell responses arise during active tuberculosis.

Avia Watson, Hao Li, Bingting Ma, Ronen Weiss, Daniele Bendayan, Lilach Abramovitz, Noam Ben-Shalom, Michael Mor, Erica Pinko, Michal Bar Oz, Zhenqiao Wang, Fengjiao Du, Yu Lu, Jan Rybniker, Rony Dahan, Hairong Huang, Daniel Barkan, Ye Xiang, Babak Javid, Natalia T. Freund