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Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis

The heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathoge...

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Autores principales: Hong, Hyejeong, Dill-McFarland, Kimberly A., Simmons, Jason D., Peterson, Glenna J., Benchek, Penelope, Mayanja-Kizza, Harriet, Boom, W. Henry, Stein, Catherine M., Hawn, Thomas R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491362/
https://www.ncbi.nlm.nih.gov/pubmed/37693490
http://dx.doi.org/10.1101/2023.08.28.23294698
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author Hong, Hyejeong
Dill-McFarland, Kimberly A.
Simmons, Jason D.
Peterson, Glenna J.
Benchek, Penelope
Mayanja-Kizza, Harriet
Boom, W. Henry
Stein, Catherine M.
Hawn, Thomas R.
author_facet Hong, Hyejeong
Dill-McFarland, Kimberly A.
Simmons, Jason D.
Peterson, Glenna J.
Benchek, Penelope
Mayanja-Kizza, Harriet
Boom, W. Henry
Stein, Catherine M.
Hawn, Thomas R.
author_sort Hong, Hyejeong
collection PubMed
description The heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis. We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in media condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of BMP6, an Mtb-dependent eQTL gene, was associated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes. These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.
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spelling pubmed-104913622023-09-09 Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis Hong, Hyejeong Dill-McFarland, Kimberly A. Simmons, Jason D. Peterson, Glenna J. Benchek, Penelope Mayanja-Kizza, Harriet Boom, W. Henry Stein, Catherine M. Hawn, Thomas R. medRxiv Article The heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis. We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion. cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in media condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of BMP6, an Mtb-dependent eQTL gene, was associated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes. These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis. Cold Spring Harbor Laboratory 2023-08-29 /pmc/articles/PMC10491362/ /pubmed/37693490 http://dx.doi.org/10.1101/2023.08.28.23294698 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Hong, Hyejeong
Dill-McFarland, Kimberly A.
Simmons, Jason D.
Peterson, Glenna J.
Benchek, Penelope
Mayanja-Kizza, Harriet
Boom, W. Henry
Stein, Catherine M.
Hawn, Thomas R.
Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis
title Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis
title_full Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis
title_fullStr Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis
title_full_unstemmed Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis
title_short Mycobacterium tuberculosis-dependent Monocyte Expression Quantitative Trait Loci and Tuberculosis Pathogenesis
title_sort mycobacterium tuberculosis-dependent monocyte expression quantitative trait loci and tuberculosis pathogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491362/
https://www.ncbi.nlm.nih.gov/pubmed/37693490
http://dx.doi.org/10.1101/2023.08.28.23294698
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