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| Status |
Public on Dec 21, 2024 |
| Title |
Dynamic Interplay of Th1/Th17 Immunity and Antimicrobial Gene Expression in Leprosy Skin Lesions |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Reversal reactions (RR) in leprosy provide a unique opportunity to study the dynamics of the immune response against intracellular bacteria in humans. We performed RNA sequencing on paired skin biopsy specimens from nine leprosy patients before and during RR, identifying a 64-gene antimicrobial response signature that correlated with the concomitant decrease in Mycobacterium leprae bacilli in RR patients. The upstream regulators of this antimicrobial gene signature included both innate (IL-1β, TNF) and adaptive (IFN-γ, IL-17) cytokines, indicating induction of both Th1 and Th17 responses. By using a machine learning classifier to identify proteins with predicted membrane-permeating activity, we identified 28 additional antimicrobial genes including S100A8. We validated the antimicrobial activity of four proteins (S100A7, S100A8, CCL17, CCL19) against M. leprae in infected macrophages and axenic culture. Scanning electron microscopy revealed distinct morphological changes in bacterial membranes upon exposure to these antimicrobial proteins. Our findings illuminate the dynamic regulation of antimicrobial gene expression as part of the innate and adaptive immune response against M. leprae and identify new potential antimicrobial effectors in human host defense. These insights underscore the potential for therapeutic strategies aimed at enhancing Th1 and Th17 cell function to improve outcomes in mycobacterial infection in humans.
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| Overall design |
We performed a longitudinal bulk-RNA-sequencing study in paired skin biopsy specimens from nine L-lep patients at the time of clinical diagnosis (pre-RR) and at the onset of RR (reversal reaction). We further confirmed our findings in skin lesions of groups of leprosy patients without multidrug therapy (MDT) that included 10 borderline-tuberculoid (T-lep), 12 RR (RR pre-MDT) and 5 new lepromatous-lepromatous (LL).
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| Contributor(s) |
Andrade PR, Ma F, Lu J, Pellegrini M, Modlin RL |
| Citation missing |
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| Submission date |
Oct 22, 2024 |
| Last update date |
Dec 21, 2024 |
| Contact name |
Priscila Ribeiro Andrade |
| E-mail(s) |
PRibeiroAndrade@mednet.ucla.edu
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| Phone |
3102062554
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| Organization name |
UCLA
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| Department |
Medicine
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| Street address |
615 Charles E Young Drive South, room 246
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| City |
Los Angeles |
| State/province |
CALIFORNIA |
| ZIP/Postal code |
90095 |
| Country |
USA |
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