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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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>M<\/jats:italic>\n                      .\n                      <jats:italic>leprae<\/jats:italic>\n                      \u2013infected macrophages and axenic cultures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      In the paired pre-RR and RR biopsy specimens, a 64-gene antimicrobial response signature was upregulated during RR and correlated with reduced\n                      <jats:italic>M<\/jats:italic>\n                      .\n                      <jats:italic>leprae<\/jats:italic>\n                      burden. Predicted upstream regulators included IL-1\u03b2, TNF, IFN-\u03b3, 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\n                      <jats:italic>M<\/jats:italic>\n                      .\n                      <jats:italic>leprae<\/jats:italic>\n                      in vitro. Scanning electron microscopy revealed membrane damage in bacteria exposed to these proteins.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>M<\/jats:italic>\n                      .\n                      <jats:italic>leprae<\/jats:italic>\n                      , suggesting potential strategies to bolster Th1 and Th17 responses for combating intracellular mycobacterial infections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci190736","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T12:00:21Z","timestamp":1750939221000},"source":"Crossref","is-referenced-by-count":9,"title":["Dynamics of Th1\/Th17 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