Human Antibodies Targeting a Transporter Mediate Protection Against Tuberculosis

Abstract

Evidence has emerged that some healthy individuals with a history of exposure to Mycobacterium tuberculosis (Mtb) can develop protective antibody responses. However, it is not known whether patients with active tuberculosis elicit protective antibodies, and if they do, which bacterial antigens are targeted. To investigate the B cell responses during active infection, we generated a panel of monoclonal antibodies isolated from memory B cells of one patient. The antibodies, members of four distinct B cell clones, were directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163 from two different B cell clones showed protective efficacy against Mtb and Mycobacterium bovis-BCG in an ex vivo human whole blood growth inhibition assay. Germline versions of p4-36 and p4-163 could no longer bind Mtb, implying that affinity maturation was vital for their activity. Crystal structures of p4-36 and a closely related clonal variant of p4-163, p4-170, complexed to PstS1 were determined at a resolution of 2.1A and 2.4A and revealed that the two antibodies recognize two distinctive epitopes on PstS1. As a proof of principle, p4-36 and p4-163 were used in a passive vaccination setting in aerosol Mtb-infected Balb/c mice, where both antibodies reduced bacterial lung burden by 50% after a single injection prior to Mtb infection. Our study shows that inhibitory B cell responses arise during active tuberculosis and identifies PstS1 as a target for elicitation of anti-Mtb antibodies.

Changes of Lymphocyte Subsets in Pulmonary Tuberculosis

“…Some scholars believed that most of the studies on PTB patients examined B cells isolated from peripheral blood and not in amed Mtbaffected tissues, which led to inconsistent conclusions on B cell levels in PTB 8 . There were experimental results to prove that inhibitory anti-PstS1 B cell responses arise during active tuberculosis 9 . The result of this study showed that the expression of B cells was higher in PTB.…”