TRANSCRIPTOMIC REANALYSIS REVEALS AUTOPHAGY, CELLULAR SENESCENCE AND MECHANOTRANSDUCTION SIGNATURES ASSOCIATED WITH PURE NEURAL LEPROSY

Pure neural leprosy (PNL) involves exclusive peripheral nerve infection by Mycobacterium leprae. Although the bacillus reprograms Schwann cells (SC), the mechanisms involved in the persistence of chronic nerve damage remain poorly understood. This study aimed to investigate molecular pathways associated with neural injury in PNL. The normalized expression matrix GSE287973 (GEO-NCBI) was reanalyzed, comprising PNL samples (n=7) and vasculitis controls (n=9). A literature-based 66-gene panel, in five modules (mechanosensors, Ca²⁺ effectors, senescence/senescence-associated secretory phenotype (SASP), autophagy, leprosy-specific SC biology), was analyzed via empirical-Bayes moderated t-test (limma-style) with Benjamini-Hochberg correction. Module scores were calculated, and Spearman's ρ was used to correlate both module scores and integrative genes, defined by literature-supported links across modules. Correlations were compared between groups by Fisher r-to-z, with exact permutation and leave-one-out validation. Significant module correlations were decomposed to single-gene level to identify drivers. Eighteen differentially expressed panel genes were identified (FDR<0.05; eleven also had FDR<0.05 in global transcriptomic analysis). Senescence/SASP genes, including CDKN1A and IL6, were upregulated in PNL, yielding a higher module score (FDR=0.03). Correlation analyses revealed relationships between PNL and controls for mechanosensors and the leprosy-specific module (ρ=0.96 vs -0.48; FDR=0.017) and autophagy and the leprosy-specific module (ρ=−0.68 vs 0.70; FDR=0.017), both surviving leave-one-out and exact permutation tests (11440 splits). Mechanotransducer PIEZO2 was identified as the main driver of this coupling (ρ=0.93 vs -0.25; exact permutation p=0.017). These findings suggest that senescence activation and a PIEZO2-linked mechanotransduction-autophagy axis emerge as candidates for understanding leprosy neuropathy and the persistence of neural lesions in PNL.