@article{ed3d63217ee1449eb656452049b5ba78,
title = "IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure",
abstract = "Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical outcomes including primary progressive tuberculosis and latent Mtb infection (LTBI). Mtb infection is identified using the tuberculin skin test and interferon-γ (IFN-γ) release assay IGRA, and a positive result may prompt chemoprophylaxis to prevent progression to tuberculosis. In the present study, we report on a cohort of Ugandan individuals who were household contacts of patients with TB. These individuals were highly exposed to Mtb but tested negative disease by IFN-γ release assay and tuberculin skin test, {\textquoteleft}resisting{\textquoteright} development of classic LTBI. We show that {\textquoteleft}resisters{\textquoteright} possess IgM, class-switched IgG antibody responses and non-IFN-γ T cell responses to the Mtb-specific proteins ESAT6 and CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classic LTBI, {\textquoteleft}resisters{\textquoteright} display enhanced antibody avidity and distinct Mtb-specific IgG Fc profiles. These data reveal a distinctive adaptive immune profile among Mtb-exposed subjects, supporting an expanded definition of the host response to Mtb exposure, with implications for public health and the design of clinical trials.",
author = "Lu, {Lenette L.} and Smith, {Malisa T.} and Yu, {Krystle K.Q.} and Corinne Luedemann and Suscovich, {Todd J.} and Grace, {Patricia S.} and Adam Cain and Yu, {Wen Han} and McKitrick, {Tanya R.} and Douglas Lauffenburger and Cummings, {Richard D.} and Harriet Mayanja-Kizza and Hawn, {Thomas R.} and Boom, {W. Henry} and Stein, {Catherine M.} and Fortune, {Sarah M.} and Chetan Seshadri and Galit Alter",
note = "Funding Information: We would like to thank the Gates Foundation for their support under the supplement no. OPP1109001 and grant nos. OPP1151840 and OPP1156795. We would also like to acknowledge the ongoing support from the Ragon Institute (to G.A. and S.M.F.) and the Samana Cay MGH scholar program to G.A. This work was supported by the following grants (grant no. K08-AI130357 to L.L.L., grant no. U01-AI115642 to W.H.B. and H.M.-K., grant no. R01-AI124348 to W.H.B., and C.M.S. and T.R.H. as multi-PI, and grant no. P41GM103694 to R.D.C.). We thank T. Ottenhoff and D. Lingwood for antigens and P. Sorger for access to the Operetta High-Content Imaging Fluorescence Microscope. We gratefully acknowledge the invaluable contribution made by the Kawempe study team{\textquoteright}s medical officers, health visitors, laboratory and data personnel in Uganda and the United States. The present study would not have been possible without the generous participation of the Ugandan patients with TB and their families. Finally, we would also like to sincerely thank the initial catalysts of this project, G. Kaplan and W. Hannekom, and K. Makar and the Gates Foundation Discovery Team for all their support. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = jun,
day = "1",
doi = "10.1038/s41591-019-0441-3",
language = "English (US)",
volume = "25",
pages = "977--987",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "6",
}