Pathogen threat proximity shapes host extracellular vesicle production in pre-infection response

Abstract

Extracellular vesicles (EVs) play a crucial role in immune responses, yet it remains unclear whether pathogen metabolites alone can stimulate EV production prior to infection. Using Caenorhabditis elegans, we investigate this question through the lens of exophers - large, evolutionarily conserved EVs known to enhance proteostasis, extend lifespan, and improve reproductive fitness. Our study uncovers distinct regulatory mechanisms driving EV production in response to pathogen-derived volatile and non-volatile metabolites, providing insights into host-pathogen signaling before physical interaction. We reveal a sophisticated network that adjusts EV production based on pathogen proximity: non-volatile metabolites, signaling an immediate threat, activate immune-dependent EV pathways, while volatile metabolites, forewarning potential danger, initiate immunity-independent exopher production. Both responses rely on sensory neurons, with ASK, ADL, and AWC neurons playing central roles in each, and additional input from ASI, AWB, and ASH neurons specifically enhancing non-volatile-induced EV production. Multiple GPCRs, including SRI-19, SRI-36, SRI-39, and SRR-6, are crucial for the non-volatile response, with signal integration mediated by the AIB interneuron and NPR-9 receptor in both responses. Notably, volatile-induced exopher production enhances offspring survival against pathogens but compromises maternal survival. Thus, our study shows that C. elegans distinguishes pathogen proximity through metabolite types, activating EV-dependent physiological responses tailored to either immediate or anticipated threats to optimize survival across generations.