TOLLIP Deficiency is Associated with Increased Mycobacterium tuberculosis -specific Anti-Microbial Monocyte Responses and Protection from Pediatric Tuberculosis in South Africa

• Published in: The Journal of immunology (1950) Vol. 196; no. 1_Supplement; pp. 193 - 193.3
• Main Authors: Shah, Javeed A, Musvosvi, Munyaradzi, Shey, Muki, Wells, Richard D., Peterson, Glenna J., Cox, Jeffrey S., Daya, Michelle, Hoal, Eileen, Gottardo, Raphael, Hanekom, Willem A., Scriba, Thomas J., Hatherill, Mark, Hawn, Thomas
• Format: Journal Article
• Language: English
• Published: 01.05.2016
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.196.Supp.193.3

Abstract Pediatric tuberculosis (TB) is a significant cause of death in children and has a different pathogenesis than adult TB, but BCG-induced immunity is incomplete. Although genetic factors regulate BCG-induced immunity and TB susceptibility, these genes are mostly unknown and have largely been unexamined in pediatric TB. We hypothesized that TOLLIP, a TLR suppressor, orchestrates immune responses to M. tuberculosis (MTb) and susceptibility to pediatric TB. We discovered that a polymorphism of TOLLIP, rs5743854, regulated signaling in a promoter assay and was associated with TOLLIP mRNA deficiency in infant peripheral blood monocytes (p = 0.008, Kruskal-Wallis). The rs5743854 G allele was associated with protection from pediatric TB in a South African cohort (N=226 cases and 626 controls, dominant model, p = 0.002, odds ratio (OR) 0.63 unadjusted analysis; p = 0.011, OR = 0.58 adjusted for ethnicity by ancestry informative markers). The G allele was also associated with decreased frequency of BCG-specific CD4+IL-2 responses (p = 0.003, Kruskal-Wallis test) and CD4+ T-cell proliferation (p = 0.03, generalized linear model) in 174 infants vaccinated with BCG at birth and re-stimulated at 10 weeks of age. To examine mechanisms of protection, we created a TOLLIP-deficient THP-1 cell line. TOLLIP-deficient monocytes had increased MTb-induced TNF and reactive nitrogen secretion and reduced MTb replication compared to control cells. Together, these data suggest that TOLLIP deficiency is associated with enhanced anti-microbial monocyte responses that control MTb replication and provide protection against pediatric TB disease. Suppressing TOLLIP levels by host-directed therapeutics may provide adjunctive therapy for pediatric TB.