The opportunistic pathogen Cutibacterium acnes could be lethal to model animal Caenorhabditis elegans both on solid agar and liquid media. C. elegans mounted a defense through PMK-1/SEK-1/TIR-1 kinase cascade. C. acnes induced the expression of several APPs. Especially, nine putatively secretory C-type lectins (clec-13, clec-17, clec-47, clec-52, clec-60, clec-61, clec-70, clec-71, and clec-227) were upregulated during infection, which are p38 MAPK pathway-dependent in C. elegans. C. elegans serves as a valuable model to study C. acnes infection-related agents in the host.