Monocyte Transcriptional Responses to Mycobacterium tuberculosis Associate with Resistance to Tuberculin Skin Test and Interferon Gamma Release Assay Conversion.

Autor:	Simmons JD; TB Research & Training Center, Department of Medicine, University of Washingtongrid.34477.33, Seattle, Washington, USA., Dill-McFarland KA; TB Research & Training Center, Department of Medicine, University of Washingtongrid.34477.33, Seattle, Washington, USA., Stein CM; Department of Population & Quantitative Health Sciences, Case Western Reserve Universitygrid.67105.35, Cleveland, Ohio, USA.; Department of Medicine, Case Western Reserve Universitygrid.67105.35, Cleveland, Ohio, USA., Van PT; Fred Hutchinson Cancer Research Centergrid.270240.3, Seattle, Washington, USA., Chihota V; School of Public Health, University of Witwatersrand, Johannesburg, South Africa.; The Aurum Institutegrid.414087.e, Parktown, South Africa., Ntshiqa T; The Aurum Institutegrid.414087.e, Parktown, South Africa., Maenetje P; The Aurum Institutegrid.414087.e, Parktown, South Africa., Peterson GJ; TB Research & Training Center, Department of Medicine, University of Washingtongrid.34477.33, Seattle, Washington, USA., Benchek P; Department of Population & Quantitative Health Sciences, Case Western Reserve Universitygrid.67105.35, Cleveland, Ohio, USA., Nsereko M; Uganda-CWRU Research Collaboration, Kampala, Uganda., Velen K; The Aurum Institutegrid.414087.e, Parktown, South Africa., Fielding KL; School of Public Health, University of Witwatersrand, Johannesburg, South Africa.; TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom., Grant AD; School of Public Health, University of Witwatersrand, Johannesburg, South Africa.; TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom.; Africa Health Research Institute, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa., Gottardo R; Fred Hutchinson Cancer Research Centergrid.270240.3, Seattle, Washington, USA.; University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland.; Swiss Institute of Bioinformatics, Lausanne, Switzerland., Mayanja-Kizza H; Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda., Wallis RS; The Aurum Institutegrid.414087.e, Parktown, South Africa., Churchyard G; School of Public Health, University of Witwatersrand, Johannesburg, South Africa.; The Aurum Institutegrid.414087.e, Parktown, South Africa.; Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA., Boom WH; Department of Medicine, Case Western Reserve Universitygrid.67105.35, Cleveland, Ohio, USA., Hawn TR; TB Research & Training Center, Department of Medicine, University of Washingtongrid.34477.33, Seattle, Washington, USA.
Jazyk:	angličtina
Zdroj:	MSphere [mSphere] 2022 Jun 29; Vol. 7 (3), pp. e0015922. Date of Electronic Publication: 2022 Jun 13.
DOI:	10.1128/msphere.00159-22
Abstrakt:	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.
Databáze:	MEDLINE
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