Format

Send to

Choose Destination
Am J Respir Crit Care Med. 2017 Aug 15;196(4):502-511. doi: 10.1164/rccm.201611-2346OC.

A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis.

Author information

1
1 University of Washington School of Medicine, Seattle, Washington.
2
2 Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
3
3 South African Tuberculosis Vaccine Initiative and.
4
4 Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
5
5 University of California Berkeley, Berkeley, California.
6
6 Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa.
7
7 Department of Statistics, Pennsylvania State University, University Park, Pennsylvania; and.
8
8 Fred Hutchinson Cancer Research Center, Seattle, Washington.

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. This 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.

KEYWORDS:

Toll-interacting protein; adaptive immunity; bacillus Calmette-Guérin; genetics; tuberculosis

PMID:
28463648
PMCID:
PMC5564674
DOI:
10.1164/rccm.201611-2346OC
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center