Antigen specificity shapes antibody functions in tuberculosis

Abstract

Tuberculosis (TB) is the number one infectious disease cause of death worldwide in part due to an incomplete understanding of immunity. Emerging data highlight antibody functions as correlates of protection and disease across human TB. However, little is known about how antibody functions impactMycobacterium tuberculosis (Mtb), the causative agent. Here, we use antigen specificity to understand how antibodies mediate host-Mtbinteractions. We focus onMtbcell wall and ESAT-6 & CFP-10, critical bacterial structural and secreted virulence proteins. In polyclonal IgG from TB patients, we observe that antigen specificity alters IgG subclass and glycosylation that drives Fc receptor binding and effector functions. Through in vitro models ofMtbmacrophage infection we find thatMtbcell wall IgG3, sialic acid, and fucose increase opsonophagocytosis of extracellularMtband bacterial burden, suggesting that some polyclonal IgG enhance disease. In contrast, ESAT-6 & CFP-10 IgG1 inhibits intracellularMtb, suggesting that antibodies targeting secreted virulence factors are protective. We test this hypothesis by generating a mAb that reacts to ESAT-6 & CFP-10 and show that it alone inhibits intracellularMtb. Understanding which antigens elicit antibody mediated disease enhancement and or protection will be critical in appreciating the many roles for antibodies in TB.