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Author Notes:

See publication for full list of authors.

Correspondence: sfortune@hsph.harvard.edu (S.M.F.), galter@mgh.harvard.edu (G.A.)

Lenette L. Lu, Amy W. Chung, Tracy Rosebrock, Sarah M. Fortune, and Galit Alter contributed equally to this work.

L.L.L., A.W.C., T.R.R., S.M.F., and G.A. conceived and planned experiments.

L.L.L., A.W.C., T.R.R., P.S.G., M.K.S., F.T., C.M., A.E.M, M.D., M.S., J.T., H.R., E.T., and K.J.F. performed experiments.

L.L.L., A.W.C., T.R.R., M.P.K., M.G., W.H.Y., D.A.L., and V.L. analyzed data.

C.D. and B.I.R. designed and conducted studies.

L.L.L., A.W.C., T.R.R., M.G., W.H.Y., D.A.L., T.J.S., H.S., C.D., B.I.R., S.M.F., and G.A. wrote the manuscript.

We thank Peter Sorger for access to 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.

Subjects:

Research Funding:

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.

This work was supported by: NIH with grants R01 AI080289 and AI102660 (GA), Dr. Dan Wattendorf and DARPA BAA-11-65 (GA), Harvard University Center for AIDS Research (CFAR) P30 AI060354 (GA, SMF, TR, MG, Ragon BL3 and Imaging Core Facility), T32 AI007387 (LL), NHMRC APP1036470 (AWC), Bill and Melinda Gates Foundation CAVD (OPP1032817: Leveraging Antibody Effector Function) (GA), Pozen Family Foundation (SMF), Doris Duke Medical Research Foundation (SMF), Burroughs Wellcome Foundation (SMF) and Ragon Institute of MGH, MIT and Harvard.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • DEPENDENT CELLULAR CYTOTOXICITY
  • FC-GAMMA RECEPTORS
  • MYCOBACTERIUM-TUBERCULOSIS
  • B-CELLS
  • MONOCLONAL-ANTIBODY
  • EFFECTOR FUNCTIONS
  • HUMORAL IMMUNITY
  • HIGH-THROUGHPUT
  • MEDIATED PROTECTION
  • VIRUS INFECTION

A Functional Role for Antibodies in Tuberculosis

Tools:

Journal Title:

Cell

Volume:

Volume 167, Number 2

Publisher:

, Pages 433-443.e14

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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.

Copyright information:

© 2016 Elsevier Inc.

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