Human Antibodies Targeting a Transporter 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. We generated 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, were directed against the Mtb phosphate transporter subunit, PstS1. Antibodies p4-36 and p4-163 reduced 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 did not bind Mtb. Crystal structures of p4-36 and p4-170 (a clonal variant of p4-163), complexed to PstS1, were determined at of 2.1Å and 2.4Å resolution, respectively, to reveal two distinctive PstS1epitopes. Lastly, a prophylactic p4-36 and p4-163 treatment in Mtb-infected Balb/c mice reduced bacterial lung burden by 50%. Sera of PstS1-immunized mice competed mostly with antibody p4-163, pointing towards the immunodominance of the p4-163 epitope over p4-36 epitope. Our study shows that inhibitory anti-PstS1 B cell responses arise during active tuberculosis and reveals new neutralizing sites on the bacteria.