BCG induced innate immune response heterogeneity and susceptibility to pediatric tuberculosis

Although immune responses to bacillus Calmette-Guerin (BCG)-vaccination and susceptibility to pediatric tuberculosis (TB) vary across individuals, the underlying cellular mechanism regulating this heterogeneity is poorly understood. We used a nested case-control study with a 2-yr prospective observation period to examine whether genetic variation is associated with BCG-induced innate immune responses and susceptibility to pediatric TB (N = 134 cases, 516 controls) in BCG-vaccinated infants. Whole blood collected at 10 wk of age from 189 control infants was stimulated with BCG or media and examined with flow cytometry to measure BCG-induced PDL1, CD40, and cytokine expression in myeloid (mDC) and plasmacytoid (pDC) dendritic cells, monocytes, and neutrophils. We used a cellular and clinical GWAS to assess for associations between genetic variants, BCG-induced innate immune responses, and susceptibility to TB. We identified 11 lead genetic variants at genome-wide level significance associated with BCG-induced cytokine and surface expression markers including PDL1 (5 pDCs, 3 mDCs, 1 monocytes), CD40 (1 mDCs), and IL-6 (1 monocytes). An IGLL1 variant (rs2096522) was associated with mDC CD40 expression (P = 1.6e-08) and was also discovered as a significant variant using a gene-based method. In the clinical GWAS, we identified 39 lead variants mapping to 74 genes suggestive of an association with susceptibility to pediatric TB (P < 1e-05), but no variant reached genome-wide significance. One clinical lead variant in the PDE8A region (rs1023844, P = 9.6e-07) was also an eQTL and associated with BCG-induced monocyte PDL1 expression. In summary, we identified genetic variants associated with heterogeneity in infant BCG-induced innate immune responses with potential immunoregulatory mechanisms.