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

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.