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Monocyte Transcriptional Responses to Mycobacterium tuberculosis Associate with Resistance to Tuberculin Skin Test and Interferon Gamma Release Assay Conversion
10.1128/msphere.00159-22
Jason D. Simmons
Kimberly A. Dill-McFarland
Catherine M. Stein
Phu T. Van
Violet Chihota
Thobani Ntshiqa
Pholo Maenetje
Glenna J. Peterson
Penelope Benchek
Mary Nsereko
Kavindhran Velen
Katherine L. Fielding
Alison D. Grant
Raphael Gottardo
Harriet Mayanja-Kizza
Robert S. Wallis
Gavin Churchyard
W. Henry Boom
Thomas R. Hawn
Research Article
tumor necrosis factor alpha
innate immunity
sequence analysis
RNA
transcriptome
host-pathogen interactions
Mycobacterium tuberculosis
American Society for Microbiology
Simmons et al.
2022
Copyright © 2022 Simmons et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
ABSTRACT
Heavy exposure to Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA); yet the mechanisms underlying this “resister” (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed transcriptome sequencing (RNA-seq) on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after ex vivo M. tuberculosis infection. Gene set enrichment analysis (GSEA) revealed several gene pathways that were consistently enriched in response to M. tuberculosis among RSTR subjects compared to controls with positive TST/IGRA testing (latent TB infection [LTBI]) across Uganda and South Africa. The most significantly enriched gene set in which expression was increased in RSTR relative to LTBI M. tuberculosis-infected monocytes was the tumor necrosis factor alpha (TNF-α) signaling pathway whose core enrichment (leading edge) substantially overlapped across RSTR populations. These leading-edge genes included candidate resistance genes (ABCA1 and DUSP2) with significantly increased expression among Uganda RSTRs (false-discovery rate [FDR], <0.1). The distinct monocyte transcriptional response to M. tuberculosis among RSTR subjects, including increased expression of the TNF signaling pathway, highlights genes and inflammatory pathways that may mediate resistance to TST/IGRA conversion and provides therapeutic targets to enhance host restriction of M. tuberculosis intracellular infection.
IMPORTANCE After heavy M. tuberculosis exposure, the events that determine why some individuals resist TST/IGRA conversion are poorly defined. Enrichment of the TNF signaling gene set among RSTR monocytes from multiple distinct cohorts suggests an important role for the monocyte TNF response in determining this alternative immune outcome. These TNF responses to M. tuberculosis among RSTRs may contribute to antimicrobial programs that result in early clearance or the priming of alternative (gamma interferon-independent) cellular responses.
20220318
20220510
20220613
2379-5042
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