Dynamics of Th1/Th17 responses and antimicrobial pathways in leprosy skin lesions
Name
190736.2-20250822153806-covered-4fa089109ce452e764bbb8648b44a723.pdf
Description
Published version
Size
15.05 MB
Format
Adobe PDF
Checksum (MD5)
1c6b7b71bdd77ccb9175c70de901dcd0
Author(s)
Andrade, Priscila R
Ma, Feiyang
Lu, Jing
de Anda, Jaime
Lee, Ernest Y
Agak, George W
Dobry, Craig J
de Andrade Silva, Bruno J
Teles, Rosane MB
Mansky, Lilah A
Date Issued
June 26, 2025
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Version
Final published version
Abstract
BACKGROUND. Reversal reactions (RRs) in leprosy are acute immune episodes marked by inflammation and bacterial clearance, offering a model to study the dynamics of host responses to Mycobacterium leprae. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. We aimed to characterize the immune mechanisms and identify antimicrobial effectors during RRs.
METHODS. We performed RNA-Seq on paired skin biopsy specimens collected from 9 patients with leprosy before and at RR diagnosis, followed by differential gene expression and functional analysis. A machine-learning classifier was applied to predict membrane-permeabilizing proteins. Antimicrobial activity was assessed in M. leprae–infected macrophages and axenic cultures.
RESULTS. In the paired pre-RR and RR biopsy specimens, a 64-gene antimicrobial response signature was upregulated during RR and correlated with reduced M. leprae burden. Predicted upstream regulators included IL-1β, TNF, IFN-γ, and IL-17, indicating activation of both the Th1 and Th17 pathways. A machine-learning classifier identified 28 genes with predicted membrane-permeabilizing antimicrobial activity, including S100A8. Four proteins (S100A7, S100A8, CCL17, and CCL19) demonstrated antimicrobial activity against M. leprae in vitro. Scanning electron microscopy revealed membrane damage in bacteria exposed to these proteins.
CONCLUSION. RR is associated with a robust antimicrobial gene program regulated by Th1 and Th17 cytokines. We identified potentially novel host antimicrobial effectors that showed activity against M. leprae, suggesting potential strategies to bolster Th1 and Th17 responses for combating intracellular mycobacterial infections.
FUNDING. NIH grants R01 AI022553, R01 AR040312, R01 AR073252, R01 AI166313, R01 AI169526, P50 AR080594, and 4R37 AI052453-21 and National Science Foundation (NSF) grant DMR2325840.
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1172/jci190736
