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 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.
Highlights
TST/IGRA negative despite high Mycobacterium tuberculosis (Mtb) exposure identified two associated chromosomal loci[14]
198 (8.3%) were PTST– upon repeated testing over 2 years of follow-up despite equivalent epidemiologic risk profiles to contacts diagnosed with latent Mtb infection (LTBI)
We demonstrate that ‘resisters’ maintain high-titer, class-switched, affinity-matured, Mtb-specific antibodies with a unique Fc profile compared with matched controls
Summary
TST/IGRA negative despite high Mtb exposure identified two associated chromosomal loci[14]. Differences in transcriptional responses to Mtb infection were found in blood monocytes from these individuals compared with individuals who develop a positive TST after similar mycobacterial exposure[15] These innate signatures point to potentially unique, first-response immunity to Mtb. From the adaptive immune perspective, the persistent lack of TST and IGRA reactivity has been interpreted as suggesting that these individuals are uninfected despite long-term close-contact exposure. Mtb-specific humoral immunity among ‘resisters’ exhibited enhanced avidity, skewing toward the IgG1 subclass selection, and distinct IgG Fc-glycosylation profiles compared with matched household contacts who converted their TST and IGRA, indicative of classic LTBI These data reveal a durable and unique adaptive immune profile after Mtb exposure not captured within the current clinical spectrum of disease and expand the range of TB responses, informing future immune correlateguided interventions
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