Genetic Variation in Toll-Interacting Protein Is Associated With Leprosy Susceptibility and Cutaneous Expression of Interleukin 1 Receptor Antagonist

Leprosy is a chronic disease characterized by skin and peripheral nerve pathology and immune responses that fail to control Mycobacterium leprae. Toll-interacting protein (TOLLIP) regulates Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling against mycobacteria. We analyzed messen...

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Bibliographic Details
Published in:The Journal of infectious diseases 2016-04, Vol.213 (7), p.1189-1197
Main Authors: Shah, Javeed A., Berrington, William R., Vary, James C., Wells, Richard D., Peterson, Glenna J., Kunwar, Chhatra B., Khadge, Saraswoti, Hagge, Deanna A., Hawn, Thomas R.
Format: Article
Language:English
Subjects:
Adult
Case-Control Studies
Gene Expression Regulation, Bacterial - physiology
Genetic Predisposition to Disease
Genotype
Humans
Interleukin 1 Receptor Antagonist Protein - genetics
Interleukin 1 Receptor Antagonist Protein - metabolism
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Leprosy - epidemiology
Leprosy - genetics
Major and Brief Reports
Mycobacterium leprae
Nepal
PATHOGENESIS AND HOST RESPONSE
Polymorphism, Single Nucleotide
Prospective Studies
Skin - metabolism
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Summary:Leprosy is a chronic disease characterized by skin and peripheral nerve pathology and immune responses that fail to control Mycobacterium leprae. Toll-interacting protein (TOLLIP) regulates Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling against mycobacteria. We analyzed messenger RNA (mRNA) expression of candidate immune genes in skin biopsy specimens from 85 individuals with leprosy. TOLLIP mRNA was highly and specifically correlated with IL-1R antagonist (IL-1Ra). In a case-control gene-association study with 477 cases and 1021 controls in Nepal, TOLLIP single-nucleotide polymorphism rs3793964 TT genotype was associated with increased susceptibility to leprosy (recessive, P= 1.4 × 10−3) and with increased skin expression of TOLLIP and IL-1Ra. Stimulation of TOLLIP-deficient monocytes with M. leprae produced significantly less IL-1Ra (P < .001), compared with control. These data suggest that M. leprae upregulates IL-1Ra by a TOLLIP-dependent mechanism. Inhibition of TOLLIP may decrease an individual's susceptibility to leprosy and offer a novel therapeutic target for IL-1–dependent diseases.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiv570