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 journalArticlepeer-review

129 Scopus citations


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 languageEnglish (US)
Pages (from-to)977-987
Number of pages11
JournalNature medicine
Issue number6
StatePublished - Jun 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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