TY - JOUR
T1 - A Functional Role for Antibodies in Tuberculosis
AU - Lu, Lenette L.
AU - Chung, Amy W.
AU - Rosebrock, Tracy R.
AU - Ghebremichael, Musie
AU - Yu, Wen Han
AU - Grace, Patricia S.
AU - Schoen, Matthew K.
AU - Tafesse, Fikadu
AU - Martin, Constance
AU - Leung, Vivian
AU - Mahan, Alison E.
AU - Sips, Magdalena
AU - Kumar, Manu P.
AU - Tedesco, Jacquelynne
AU - Robinson, Hannah
AU - Tkachenko, Elizabeth
AU - Draghi, Monia
AU - Freedberg, Katherine J.
AU - Streeck, Hendrik
AU - Suscovich, Todd J.
AU - Lauffenburger, Douglas A.
AU - Restrepo, Blanca I.
AU - Day, Cheryl
AU - Fortune, Sarah M.
AU - Alter, Galit
N1 - Funding Information:
CEM.NKR-CCR5 was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. The following reagents were obtained through BEI Resources, NIAID, NIH: cell membrane, culture filtrate, cytosol protein, soluble cell wall protein, and soluble protein fractions of H37RV M. tuberculosis. We thank Peter Sorger for access to the Operetta High-Content Imaging Fluorescence Microscope; Rebecca Gelman, Director of the Harvard Center for AIDS Biostatistics Core, for her advice; and many additional members of the SATVI team who helped with enrollment and evaluation of participants. This work was supported by the NIH (grants R01 AI080289 and AI102660, to G.A.), Dr. Dan Wattendorf and DARPA BAA-11-65 (G.A.), Harvard University Center for AIDS Research (CFAR) grant P30 AI060354 (to G.A., S.M.F., T.R., and M.G., Ragon BL3 and Imaging Core Facility), grant T32 AI007387 (to L.L.L.), NHMRC APP1036470 (A.W.C.), Bill and Melinda Gates Foundation CAVD (OPP1032817: Leveraging Antibody Effector Function) (G.A.), the Pozen Family Foundation (S.M.F.), the Doris Duke Medical Research Foundation (S.M.F.), the Burroughs Wellcome Foundation (S.M.F.), and the Ragon Institute of MGH, MIT, and Harvard.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/6
Y1 - 2016/10/6
N2 - While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.
AB - While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.
KW - Fc-receptors
KW - antibodies
KW - inflammasome
KW - innate immunity
KW - tuberculosis
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U2 - 10.1016/j.cell.2016.08.072
DO - 10.1016/j.cell.2016.08.072
M3 - Article
C2 - 27667685
AN - SCOPUS:84990842088
SN - 0092-8674
VL - 167
SP - 433-443.e14
JO - Cell
JF - Cell
IS - 2
ER -