University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Department of Microbiology and Physiological Systems; Department of Medicine, Division of Infectious Diseases and Immunology
Publication Date
2021-03-06
Document Type
Article Preprint
Disciplines
Amino Acids, Peptides, and Proteins | Bacterial Infections and Mycoses | Immunity | Immunology of Infectious Disease | Immunopathology | Infectious Disease | Microbiology
Abstract
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.
Keywords
Infectious Diseases, CNBP, REL, BHLHE40, dendritic cells, genetics, M. tuberculosis
Rights and Permissions
The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
10.1101/2021.03.03.21252797
Source
medRxiv 2021.03.03.21252797; doi: https://doi.org/10.1101/2021.03.03.21252797. Link to preprint on medRxiv.
Journal/Book/Conference Title
medRxiv
Repository Citation
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
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Bacterial Infections and Mycoses Commons, Immunity Commons, Immunology of Infectious Disease Commons, Immunopathology Commons, Infectious Disease Commons, Microbiology Commons
Comments
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
Full author list omitted for brevity. For the full list of authors, see article.