Dynamics of Th1/Th17 Responses and Antimicrobial Pathways in Leprosy Skin Lesions

Reversal reactions (RR) in leprosy provide a unique opportunity to study the dynamics of the immune response against intracellular bacteria in humans. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. 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 signature included both innate (IL-1β, TNF) and adaptive (IFN-γ, IL-17) cytokines, indicating induction of both Th1 and Th17 responses. Using a machine learning classifier to identify proteins with predicted membrane-permeating activity, we identified 28 genes in RR with previously unknown direct antimicrobial activity, 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 membrane damage in bacteria exposed to these antimicrobial proteins. Our findings reveal dynamic antimicrobial gene regulation during RR and identify new host defense effectors, supporting therapeutic strategies that boost Th1/Th17 function to improve outcomes in mycobacterial infections.