Department of Microbiology and Physiological Systems; Department of Medicine, Division of Infectious Diseases and Immunology
Amino Acids, Peptides, and Proteins | Bacterial Infections and Mycoses | Immunity | Immunology of Infectious Disease | Immunopathology | Infectious Disease | Microbiology
Rationale: The major human genes regulating M. tuberculosis (Mtb)-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling.
Objectives: To determine whether common human genetic variation in CNBP, REL and BHLHE40 is associated with IL-12 and IL-10 expression, adaptive immune responses to mycobacteria, and susceptibility to TB.
Methods and Main Measurements: We characterized the association between common variants in CNBP, REL, and BHLHE40 and innate immune responses in dendritic cells and monocyte-derived macrophages (MDM), BCG-specific T cell responses, and susceptibility to pediatric and adult TB.
Results: SNP BHLHE40 rs4496464 was associated with increased BHLHE40 expression in MDMs and increased IL-10 from both peripheral blood dendritic cells and MDMs after LPS and TB whole cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and CNBP rs11709852 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618, in linkage disequilibrium with rs842634, was associated with increased risk for TB meningitis.
Conclusions: Genetic variation in CNBP, REL, and BHLHE40 is associated with IL-12 and IL-10 cytokine response and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.
Infectious Diseases, CNBP, REL, BHLHE40, dendritic cells, genetics, M. tuberculosis
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DOI of Published Version
medRxiv 2021.03.03.21252797; doi: https://doi.org/10.1101/2021.03.03.21252797. Link to preprint on medRxiv.
Shah JA, Sassetti CM, Fitzgerald KA. (2021). CNBP, REL, and BHLHE40 variants are associated with IL-12 and IL-10 responses and tuberculosis risk [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2021.03.03.21252797. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1923
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