IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure

Lenette L. Lu; Malisa T. Smith; Krystle K.Q. Yu; Corinne Luedemann; Todd J. Suscovich; Patricia S. Grace; Adam Cain; Wen Han Yu; Tanya R. McKitrick; Douglas Lauffenburger; Richard D. Cummings; Harriet Mayanja-Kizza; Thomas R. Hawn; W. Henry Boom; Catherine M. Stein; Sarah M. Fortune; Chetan Seshadri; Galit Alter

doi:10.1038/s41591-019-0441-3

IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure

Lenette L. Lu, Malisa T. Smith, Krystle K.Q. Yu, Corinne Luedemann, Todd J. Suscovich, Patricia S. Grace, Adam Cain, Wen Han Yu, Tanya R. McKitrick, Douglas Lauffenburger, Richard D. Cummings, Harriet Mayanja-Kizza, Thomas R. Hawn, W. Henry Boom, Catherine M. Stein, Sarah M. Fortune, Chetan Seshadri, Galit Alter

Research output: Contribution to journal › Article › peer-review

139 Scopus citations

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, ‘resisting’ development of classic LTBI. We show that ‘resisters’ 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, ‘resisters’ 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.

Original language	English (US)
Pages (from-to)	977-987
Number of pages	11
Journal	Nature medicine
Volume	25
Issue number	6
DOIs	https://doi.org/10.1038/s41591-019-0441-3
State	Published - Jun 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Lu, L. L., Smith, M. T., Yu, K. K. Q., Luedemann, C., Suscovich, T. J., Grace, P. S., Cain, A., Yu, W. H., McKitrick, T. R., Lauffenburger, D., Cummings, R. D., Mayanja-Kizza, H., Hawn, T. R., Boom, W. H., Stein, C. M., Fortune, S. M., Seshadri, C., & Alter, G. (2019). IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure. Nature medicine, 25(6), 977-987. https://doi.org/10.1038/s41591-019-0441-3

Lu, LL, Smith, MT, Yu, KKQ, Luedemann, C, Suscovich, TJ, Grace, PS, Cain, A, Yu, WH, McKitrick, TR, Lauffenburger, D, Cummings, RD, Mayanja-Kizza, H, Hawn, TR, Boom, WH, Stein, CM, Fortune, SM, Seshadri, C & Alter, G 2019, 'IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure', Nature medicine, vol. 25, no. 6, pp. 977-987. https://doi.org/10.1038/s41591-019-0441-3

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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",

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AU - Grace, Patricia S.

AU - Cain, Adam

AU - Yu, Wen Han

AU - McKitrick, Tanya R.

AU - Lauffenburger, Douglas

AU - Cummings, Richard D.

AU - Mayanja-Kizza, Harriet

AU - Hawn, Thomas R.

AU - Boom, W. Henry

AU - Stein, Catherine M.

AU - Fortune, Sarah M.

AU - Seshadri, Chetan

AU - Alter, Galit

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N2 - 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, ‘resisting’ development of classic LTBI. We show that ‘resisters’ 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, ‘resisters’ 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.

AB - 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, ‘resisting’ development of classic LTBI. We show that ‘resisters’ 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, ‘resisters’ 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.

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IFN-γ-independent immune markers of Mycobacterium tuberculosis exposure

Abstract

ASJC Scopus subject areas

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