Pathogen Subversion of Neuro-Epidermal Signaling Impairs Lysosomal Function to Disrupt Collagen Homeostasis

The epidermis relies on collagen-rich extracellular matrices (ECMs) to maintain barrier integrity against pathogens. Lysosomes regulate cuticle collagen turnover, yet how neuronal signaling modulates epidermal lysosomal function and collagen organization during infection remains unclear. Using Pseudomonas aeruginosa PA14-Caenorhabditis elegans infection model, we demonstrate that pathogen-induced neuronal signaling disrupts epidermal lysosomal activity and collagen remodeling. PA14 infection triggers neurons to secrete NSIF-1 (Neuronal Secreted Immune Factor 1), which translocates to the epidermis and impairs lysosomal acidification, maturation, and degradation by suppressing the transcription factor ELT-3. This disruption leads to disorganized collagen structure, compromising cuticle integrity and host resistance. Genetic mutation of nsif-1 restores lysosomal function, enhances collagen density, and improves survival, while neuron-specific nsif-1 deletion confirms its neuronal origin. Moreover, NSIF-1 inhibits ELT-3 nuclear localization, blocking its role in lysosomal-dependent ECM repair. Our study reveals a neuro-epidermal axis wherein pathogens exploit neuronal signals to disrupt lysosomal function and collagen homeostasis, identifying NSIF-1 and ELT-3 as potential targets to counteract infection-driven ECM dysregulation. SignificancePathogens often hijack host signaling networks to evade immunity, but how they manipulate neuronal-epidermal crosstalk to disrupt ECM remodeling remains unknown. We demonstrate that P. aeruginosa PA14 induces neurons to secrete the neuropeptide-like factor NSIF-1, which suppresses epidermal lysosomal acidification and proteolytic function. This impairment disrupts collagen organization by blocking ELT-3/GATA-mediated lysosomal gene expression, creating a permissive niche for infection. Strikingly, NSIF-1 operates as a neuroimmune checkpoint, differentially regulating PMK-1/p38-mediated intestinal immunity and ELT-3-dependent epidermal lysosomal function to coordinate tissue-specific susceptibility. The identification of NSIF-1 and ELT-3 opens avenues for host-directed therapies to counteract pathogen-induced matrix dysregulation, with implications for chronic infections and collagenopathies.