A Functional Role for Antibodies in Tuberculosis.
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.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Lenette L
LL
Lu
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Amy W
AW
Chung
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Tracy R
TR
Rosebrock
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Musie
M
Ghebremichael
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Wen Han
WH
Yu
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Patricia S
PS
Grace
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Matthew K
MK
Schoen
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Fikadu
F
Tafesse
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Constance
C
Martin
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Vivian
V
Leung
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Alison E
AE
Mahan
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Biomedical Molecular Biology, Ghent University, Ghent 9000, Belgium.
Magdalena
M
Sips
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Manu P
MP
Kumar
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Jacquelynne
J
Tedesco
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Hannah
H
Robinson
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Elizabeth
E
Tkachenko
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Monia
M
Draghi
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Katherine J
KJ
Freedberg
Institute for Medical Biology, University Hospital Essen, University of Duisburg-Essen, 45141 Essen, Germany.
Hendrik
H
Streeck
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Todd J
TJ
Suscovich
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Douglas A
DA
Lauffenburger
School of Public Health, University of Texas Health Houston, Brownsville, TX 78520, USA.
Blanca I
BI
Restrepo
Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30307, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30332, USA; South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa.
Cheryl
C
Day
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. Electronic address: sfortune@hsph.harvard.edu.
Sarah M
SM
Fortune
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address: galter@mgh.harvard.edu.
Galit
G
Alter
D000328:Adult; D000907:Antibodies, Bacterial / Q000276:immunology*; D005260:Female; D006031:Glycosylation; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D055985:Latent Tuberculosis / Q000276:immunology*; D008262:Macrophage Activation; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011134:Polysaccharides / Q000276:immunology; D040081:Protein Array Analysis; D017452:Receptors, IgG / Q000276:immunology; D055815:Young Adult
D000907:Antibodies, Bacterial; C496124:FCGR3A protein, human; D007141:Immunoglobulin Fc Fragments; D011134:Polysaccharides; D017452:Receptors, IgG
Fc-receptors; antibodies; inflammasome; innate immunity; tuberculosis
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