Decoding Host–Pathogen Interactions Through Caenorhabditis elegans : A Narrative Case Study

Infectious diseases continue to pose a significant challenge to global health, particularly with the emergence of multidrug‐resistant pathogens. Understanding host–pathogen interactions (HPIs) is fundamental to uncovering mechanisms of infection, immunity, and adaptation. This narrative review provides a panoramic view of molecular and systems‐level insights into host defense and pathogen virulence, emphasizing Caenorhabditis elegans as a versatile in vivo model. Studies from our laboratory and others highlight how conserved immune modules, including p38 MAPK, JNK‐MAPK, TGF‐ β , and insulin/IGF‐1 signaling, mediate survival, stress adaptation, and longevity during bacterial infection. Transcriptomic, proteomic, and metabolomic investigations reveal infection‐induced remodeling of proteostasis, energy metabolism, and post‐translational regulations. Recent metabolomics and transgenerational studies demonstrate how pathogens influence neural, reproductive, and metabolic networks to generate heritable adaptive traits. Integrating findings across multiple systems, such as C. elegans , Drosophila , Zebrafish, and mammalian organoid systems, establishes a translational continuum linking innate and adaptive immunity. Emerging frameworks such as the Host–Pathogen Interaction Phenotype Ontology (HPIPO) and AI‐driven multiomic modeling enable predictive mapping of infection outcomes. Collectively, these advances transform infection biology from descriptive observation to a data‐driven, systems immunology discipline, offering new avenues for precision antimicrobial or anti‐infective development, vaccine design, and therapeutic interventions.