A functional toll-interacting protein variant is associated with bacillus calmette-guérin-specific immune responses and tuberculosis

Javeed A. Shah, Munyaradzi Musvosvi, Muki Shey, David J. Horne, Richard D. Wells, Glenna J. Peterson, Jeffery S. Cox, Michelle Daya, Eileen G. Hoal, Lin Lin, Raphael Gottardo, Willem A. Hanekom, Thomas J. Scriba, Mark Hatherill, Thomas R. Hawn

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Rationale: The molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibility to tuberculosis, but the mechanism by which it regulates tuberculosis immunity is poorly understood. Objectives: To identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis. Methods: We used human cellular immunology approaches to characterize the role of a functional TOLLIP variant on monocyte mRNA expression and M. tuberculosis-induced monocyte immune functions. We also examined the association of TOLLIP variation with BCG-induced T-cell responses and susceptibility to latent tuberculosis infection. Measurements and Main Results: We identified a functional TOLLIP promoter region single-nucleotide polymorphism, rs5743854, which was associated with decreased TOLLIP mRNA expression in infant monocytes. After M. tuberculosis infection, TOLLIP-deficient monocytes demonstrated increased IL-6, increased nitrite, and decreased bacterial replication. The TOLLIP-deficiency G/G genotype was associated with decreased BCG-specific IL-2+ CD4+ T-cell frequency and proliferation. his genotype was also associated with increased susceptibility to latent tuberculosis infection. Conclusions: TOLLIP deficiency is associated with decreased BCG-specific T-cell responses and increased susceptibility to tuberculosis. We hypothesize that the heightened antibacterial monocyte responses after vaccination of TOLLIP-deficient infants are responsible for decreased BCG-specific T-cell responses. Activating TOLLIP may provide a novel adjuvant strategy for BCG vaccination.

Original languageEnglish (US)
Pages (from-to)502-511
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume196
Issue number4
DOIs
StatePublished - Aug 15 2017

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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