A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis
Shah, JA; Musvosvi, M; Shey, M; Horne, DJ; Wells, RD; Peterson, GJ; Cox, JS; Daya, M; Hoal, EG; Lin, L; Gottardo, R; Hanekom, WA; Scriba, TJ; Hatherill, M; Hawn, TR
| HERO ID | 4132505 |
|---|---|
| In Press | No |
| Year | 2017 |
| Title | A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis |
| Authors | Shah, JA; Musvosvi, M; Shey, M; Horne, DJ; Wells, RD; Peterson, GJ; Cox, JS; Daya, M; Hoal, EG; Lin, L; Gottardo, R; Hanekom, WA; Scriba, TJ; Hatherill, M; Hawn, TR |
| Journal | American Journal of Respiratory and Critical Care Medicine |
| Volume | 196 |
| Issue | 4 |
| Page Numbers | 502-511 |
| Abstract | <strong>RATIONALE: </strong>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.<br /><br /><strong>OBJECTIVES: </strong>To identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis.<br /><br /><strong>METHODS: </strong>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.<br /><br /><strong>MEASUREMENTS AND MAIN RESULTS: </strong>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.<br /><br /><strong>CONCLUSIONS: </strong>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. |
| Doi | 10.1164/rccm.201611-2346OC |
| Pmid | 28463648 |
| Wosid | WOS:000407532700017 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |