Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model

Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.

Authors

Institutions

Publication Details

Journal
ImmunoHorizons
Published
2024-09-01
DOI
https://doi.org/10.4049/immunohorizons.2400053
Citations
1
Primary Topic
T-cell and B-cell Immunology
Type
article
Field-Weighted Citation Impact
0.24

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model

Lamar Ballweber-Fleming, One Dintwe, Elizabeth Church, James G. Kublin et al.
1 citations
ImmunoHorizons
T-cell and B-cell Immunology
0.24
article

Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model

Lamar Ballweber-Fleming, One Dintwe, Elizabeth Church, James G. Kublin, Valentin Voillet, Georgia D. Tomaras, Gift Nwanne, Jolie M. Phan, Andrew Fioré-Gartland, Mohau S. Makatsa, Jay C. Vary, Emma Bishop, Ming Chang, Sean C. Murphy, Krystle K. Q. Yu, Koshlan Mayer-Blackwell, Jack Heptinstall, Erica Andersen‐Nissen, Kelvin Chiong, M. Juliana McElrath, Chetan Seshadri, David R. Sherman, Anneta Naidoo, Justin K. Brache, Richard M. Jones
article en
1 citations

Abstract

Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.

ImmunoHorizonsVol. 8(9)
Public Health – Seattle & King County (US), Duke University (US), University of Washington (US), Fred Hutch Cancer Center (US), Cape Town Science Centre (ZA)
National Institutes of Health
Good health and well-being
Openalex Percentile: Top 42%
T-cell and B-cell Immunology
0.24
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.