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

Area of Science:

• Immunology
• Cell Biology
• Neuroscience

Background:

• The skin's epidermis requires collagen-rich extracellular matrices (ECMs) for barrier function against pathogens.
• Lysosomes are crucial for regulating collagen turnover, but the role of neuronal signaling in this process during infection is unknown.

Purpose of the Study:

• To investigate how neuronal signaling affects epidermal lysosomal function and collagen organization during infection.
• To elucidate the molecular mechanisms underlying pathogen-induced disruption of host defense.

Main Methods:

• Utilized a *Pseudomonas aeruginosa* PA14-*Caenorhabditis elegans* infection model.
• Investigated the role of Neuronal Secreted Immune Factor 1 (NSIF-1) and transcription factor ELT-3 in neuro-epidermal communication.
• Employed genetic mutations and neuron-specific knockdown to assess NSIF-1 function.

Main Results:

• Pathogen infection triggers neuronal secretion of NSIF-1, which impairs epidermal lysosomal acidification, maturation, and degradation.
• NSIF-1 suppresses ELT-3, leading to disorganized collagen structure, compromised cuticle integrity, and reduced host resistance.
• Genetic inactivation of *nsif-1* restored lysosomal function, enhanced collagen density, and improved survival.

Conclusions:

• Pathogens exploit a neuro-epidermal axis, using neuronal signals like NSIF-1 to disrupt lysosomal function and collagen homeostasis.
• NSIF-1 inhibits ELT-3's nuclear localization, blocking lysosomal-dependent ECM repair.
• NSIF-1 and ELT-3 are potential therapeutic targets for combating infection-induced ECM dysregulation.